Pyrrolo[1,2-b] pyridazine derivatives having sPLA2 inhibitory effect

ABSTRACT

The present invention provides a compound having sPLA 2  inhibiting activity. 
     The compound represented by the formula (I):                    
     wherein R 1  is —(L 1 )—R 6  wherein L 1  is a divalent linking group of 1 to 18 atoms or the like, and R 6  is a carbocyclic ring substituted by at least one non-interfering substituent or the like; R 2  is C1 to C3 alkyl or the like; R 3  is —(L 2 )-(acidic group); R 4  and R 5  are hydrogen atoms, non-interfering substituents, carbocyclic groups or the like; X is independently oxygen atom of sulfur atom; and R A  is —C(═X)—C(═X)—NH 2  or the like; the prodrugs thereof, their pharmaceutically acceptable salts, or their solvates, and a composition for inhibiting sPLA 2  containing them as effective ingredients.

TECHNICAL FIELD

The present invention relates to a pyrrolo[1,2-b]pyridazine derivative effective for inhibiting sPLA₂-mediated fatty acid release.

BACKGROUND ART

sPLA₂ (secretory phospholipase A₂) is an enzyme that hydrolyzes membrane phospholipids and has been considered to be a rate-determining enzyme that governs the so-called arachidonate cascade where arachidonic acid, the hydrolysis product, is the starting material. Moreover, lysophospholipids that are produced as by-products in the hydrolysis of phospholipids have been known as important mediators in cardiovascular diseases. Accordingly, in order to normalize excess functions of the arachidonate cascade and the lysophospholipids, it is important to develop compounds which inhibit the liberation of sPLA₂-mediated fatty acids (for example, arachidonic acid), namely, compounds which inhibit the activity or production of sPLA₂. Such compounds are useful for general treatment of symptoms, which are induced and/or sustained by an excess formation of sPLA₂, such as septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arteriosclerosis, cerebral apoplexy, cerebral infarction, inflammatory colitis, psoriasis, cardiac insufficiency, cardiac infarction, and so on. The participation of sPLA₂ is considered to be extremely wide and, besides, its action is potent.

There are known, as examples of sPLA₂ inhibitor, indole derivatives in EP-620214 (JP Laid-Open No. 010838/95), EP-620215 (JP Laid-Open No. 025850/95), EP-675110 (JP Laid-Open No. 285933/95), WO 96/03376, and WO 99/00360; indene derivatives in WO 96/03120; indolizine derivatives in WO 96/03383; naphthalene derivatives in WO 97/21664 and WO 97/21716; tricyclic derivatives in WO 98/18464; pyrazole derivatives in WO 98/24437; phenylacetamide derivatives in WO 98/24756; phenyl glyoxamide derivatives in WO 98/24794; pyrrole derivatives in WO 98/25609.

DISCLOSURE OF INVENTION

The present invention provides pyrrolo[1,2-b]pyridazine derivatives having sPLA₂ inhibiting activity and being useful for treatment of septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arterial sclerosis, cerebral hemorrhage, cerebral infarction, inflammatory colitis, psoriasis, cardiac failure, and cardiac infarction.

The present invention relates to i) a compound represented by the formula (I):

wherein R¹ is a group selected from (a) C6 to C20 alkyl, C6 to C20 alkenyl, C6 to C20 alkynyl, carbocyclic groups, and heterocyclic groups, (b) the groups represented by (a) each substituted independently with at least one group selected from non-interfering substituents, and (c) —(L¹)—R⁶ wherein L¹ is a divalent linking group of 1 to 18 atom(s) selected from hydrogen atom(s), nitrogen atom(s), carbon atom(s), oxygen atom(s), and sulfur atom(s), and R⁶ is a group selected from the groups (a) and (b);

R² is hydrogen atom or a group containing 1 to 4 non-hydrogen atoms;

R³ is —(L²)-(acidic group) wherein L² is an acid linker having an acid linker length of 1 to 5;

R⁴ and R⁵ are selected independently from hydrogen atom, non-interfering substituents, carbocyclic groups, carbocyclic groups substituted with a non-interfering substituent(s), heterocyclic groups, and heterocyclic groups substituted by a non-interfering substituent(s); and

R^(A) is a group represented by the formula:

 wherein L⁷ is a divalent linker group selected from a bond or a divalent group selected from —CH₂—, —O—, —S—, —NH—, or —CO—, R²⁷ and R²⁸ are independently hydrogen atom, C1 to C3 alkyl or a halogen; X and Y are independently an oxygen atom or a sulfur atom; and Z is —NH₂ or —NHNH₂; the prodrugs thereof, or their pharmaceutically acceptable salts; or their solvates.

In more detail, the present invention relates to ii) a compound represented by the formula (II):

where R⁷ is —(CH₂)m—R² wherein m is an integer from 1 to 6, and R¹² is (d) a group represented by the formula:

wherein a, c, e, n, q, and t are independently an integer from 0 to 2, R¹³ and R¹⁴ are independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heteroaryl, and C1 to C1 0 haloalkyl, α is an oxygen atom or a sulfur atom, L⁵ is —(CH₂)v—, —C═C—, —C≡C—, —O—, or —S—, v is an integer from 0 to 2, β is —CH₂— or —(CH₂)₂—, γ is an oxygen atom or a sulfur atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, g is an integer from 0 to 2, r is an integer from 0 to 7, and u is an integer from 0 to 4, or is (e) a member of (d) substituted with at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 haloalkyloxy, C1 to C6 haloalkyl, aryl, and a halogen;

R⁸ is C1 to C3 alkyl, C2 to C3 alkenyl, C3 to C4 cycloalkyl, C3 to C4 cycloalkenyl, C1 to C2 haloalkyl, C1 to C3 alkyloxy, or C1 to C3 alkylthio;

R⁹ is —(L³)—R¹⁵ wherein L³ is represented by the formula:

 wherein M is —CH₂—, —O—, —N(R²⁴)—, or —S—, R¹⁶ and R¹⁷ are independently hydrogen atom, C1 to C10 alkyl, aryl, aralkyl, alkyloxy, haloalkyl, carboxy, or a halogen, and R²⁴ is hydrogen atom or C1 to C6 alkyl, and R¹⁵ is represented by the formula:

 wherein R¹⁸ is hydrogen atom, a metal, or C1 to C10 alkyl, R¹⁹ is independently hydrogen atom, or C1 to C10 alkyl, and t is an integer from 1 to 8;

R¹⁰ and R¹¹ are independently hydrogen atom or a non-interfering substituent selected from C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C7 to C12 aralkyl, C7 to C12 alkaryl, C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenylyl, C1 to C8 alkyloxy, C2 to C8 alkenyloxy, C2 to C8 alkynyloxy, C2 to C12 alkyloxyalkyl, C2 to C12 alkyloxyalkyloxy, C2 to C12 alkylcarbonyl, C2 to C12 alkylcarbonylamino, C2 to C12 alkyloxyamino, C2 to C12 alkyloxyaminocarbonyl, C1 to C12 alkylamino, C1 to C6 alkylthio, C2 to C12 alkylthiocarbonyl, C1 to C8 alkylsulfinyl, C1 to C8 alkylsulfonyl, C2 to C8 haloalkyloxy, C1 to C8 haloalkylsulfonyl, C2 to C8 haloalkyl, C1 to C8 hydroxyalkyl, —C(O)O(C1 to C8 alkyl), —(CH₂)_(z)—O—(C1 to C8 alkyl), benzyloxy, aryloxy, aryloxy C1 to C8 alkyl, arylthio, arylthio C1 to C8 alkyl, cyano C1 to C8 alkyl, —(CONHSO₂R²⁵), —CHO, amino, amidino, halogen, carbamyl, carboxyl, carbalkoxy, —(CH₂)_(z)—CO₂H, cyano, cyanoguanidinyl, guanidino, hydrazido, hydrazino, hydrazide, hydroxy, hydroxyamino, iodo, nitro, phosphono, —SO₃H, thioacetal, thiocarbonyl, or carbonyl, R²⁵ is C1 to C6 alkyl or aryl, z is an integer from 1 to 8; and R^(B) is a group represented by the formula:

 wherein Z is the same as defined above; the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates.

When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R¹³ or R¹⁴ may be different from one another. When R¹³ is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group.

iii) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in above i) or ii), wherein said R¹ and R⁷ are independently represented by the formula:

wherein R¹³, R¹⁴, b, d, f, g, p, r, u, w, α, β, and γ are the same as defined above, L⁶ is a bond, —CH₂—, —C═C—, —C≡C—, —O—, or —S—.

When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R¹³ or R¹⁴ may be different from one another. When R¹³ is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group.

iv) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in any one of i) to iii), wherein R² and R⁸ are C1 to C3 alkyl or C3 to C4 cycloalkyl.

v) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in any one of i) to iv), wherein the L² and L³ are —O—CH₂—.

vi) A compound represented by the formula (III):

wherein R²⁰ is a group represented by the formula:

wherein L⁶ is a bond, —CH₂—, —C═C—, —C≡C—, —O—, or —S—; R¹³ and R¹⁴ are independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heteroaryl, and C1 to C10 haloalkyl; b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, g is an integer from 0 to 2, r is an integer from 0 to 7, u is an integer from 0 to 4; α is an oxygen atom or a sulfur atom; β is —CH₂— or —(CH₂)₂—; and γ is an oxygen atom or a sulfur atom;

R²¹ is C1 to C3 alkyl or C3 to C4 cycloalkyl;

L⁴ is —O—CH₂—, —S—CH₂—, —N(R²⁴)—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—, or —O—CH((CH₂)₂Ph)— wherein R²⁴ is hydrogen atom or C1 to C6 alkyl and Ph is phenyl;

R²² is —COOH, —SO₃H, or P(O)(OH)₂;

R²³ is hydrogen atom, C1 to C6 alkyl, C7 to C12 aralkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, C1 to C6 hydroxyalkyl, C2 to C6 haloalkyloxy, halogen, carboxy, C1 to C6 alkyloxycarbonyl, aryloxy, aryloxy C1 to C8 alkyl, arylthio, arylthio C1 to C8 alkyl, cyano C1 to C8 alkyl, a carbocyclic group, or a heterocyclic group; and

R^(B) is a group represented by the formula:

 wherein Z is —NH₂ or —NHNH₂; the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates.

When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R¹³ or R¹⁴ may be different from one another. When R¹³ is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group.

vii) A compound represented by the formula (IV):

wherein R²⁰ is a group represented by the formula:

wherein L⁶ is a bond, —CH₂—, —C═C—, —C≡C—, —O—, or —S—; R¹³ and R¹⁴ are independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heteroaryl, and C1 to C10 haloalkyl; b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, g is an integer from 0 to 2, r is an integer from 0 to 7, u is an integer from 0 to 4; α is an oxygen atom or a sulfur atom; β is —CH₂— or —(CH₂)₂—; and γ is an oxygen atom or a sulfur atom;

R²¹ is C1 to C3 alkyl or C3 to C4 cycloalkyl;

R²³ is hydrogen atom, C1 to C6 alkyl, C7 to C12 aralkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, C1 to C6 hydroxyalkyl, C2 to C6 haloalkyloxy, halogen, carboxy, C1 to C6 alkyloxycarbonyl, aryloxy, aryloxy C1 to C8 alkyl, arylthio, arylthio C1 to C8 alkyl, cyano C1 to C8 alkyl, a carbocyclic group, or a heterocyclic group;

R^(B) is a group represented by the formula:

 wherein Z is —NH₂ or —NHNH₂; and

k is an integer from 1 to 3; the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates.

viii) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in vi), wherein L⁴ is —O—CH₂—.

ix) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in any one of i) to viii), wherein R^(A) and R^(B) are —COCONH₂—.

x) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in any one of i) to viii), wherein R^(A) and R^(B) are —CH₂CONH₂—.

xi) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in any one of i) to viii) wherein R^(A) and R^(B) are —CH₂CONHNH₂—.

xii) A prodrug as described in any one of i) to viii) which of an is ester type.

xiii) A pyrrolo[1,2-b]pyridazine compound selected from the group consisting of:

Methyl (5-aminooxalyl-7-benzyl-6-ethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

(5-aminooxalyl-7-benzyl-6-ethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,

Sodium (5-aminooxalyl-7-benzyl-6-ethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

Methyl (5-aminooxalyl-7-benzyl-6-ethyl-2-methylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

(5 -aminooxalyl-7-benzyl-6-ethyl-2-methylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,

Methyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy) acetate,

Ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy) acetate,

2-(Morpholine4-yl)ethyl (5aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

(5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,

Sodium (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

Methyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

(5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,

Methyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

(5-aminooxalyl-7-benzyl-6-ethyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,

Methyl [5-aminooxalyl-6-ethyl-7-(2-fluorobenzyl)-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy]acetate,

[5-aminooxalyl-6-ethyl-7-(2-fluorobenzyl)-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid,

Methyl [5-aminooxalyl-7-benzyl-6-ethyl-2-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,

[5-aminooxalyl-7-benzyl-6-ethyl-2-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid,

Methyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

(5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine4-yloxy)acetic acid,

Methyl [5-aminooxalyl-7-benzyl-6-ethyl-2-(4-methoxyphenyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,

[5-aminooxalyl-7-benzyl-6-ethyl-2-(4-methoxyphenyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid,

Methyl [5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,

[5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid,

Methyl [5-aminooxalyl-6-ethyl-2-methyl-7-(3-phenoxybenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,

[5-aminooxalyl-6-ethyl-2-methyl-7-(3 -phenoxybenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid,

Methyl (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

(5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,

Methyl (5-aminooxalyl-2,7-dibenzyl-6-methylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

(5-aminooxalyl-2,7-dibenzyl-6-methylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,

Methyl [5-aminooxalyl-2,6-dimethyl-7-[2-(4-fluorophenyl)benzyl]pyrrolo[1,2-b]pyridazine-4-yloxy]acetate, and

[5-aminooxalyl-2,6-dimethyl-7-[2-(4-fluorophenyl)benzyl]pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid,

and the prodrugs thereof; or their pharmaceutically acceptable salts; their parent acids; or their solvates.

xiv) A pyrrolo[1,2-b]pyridazine compound selected from the group consisting of:

Methyl(5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

Ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine4-yloxy)acetate,

2-(Morpholine-4-yl)ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

Sodium (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

(5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,

Methyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

Ethyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

2-(Morpholine-4-yl)ethyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo [1,2-b]pyridazine-4-yloxy)acetate,

Sodium (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

(5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,

Methyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

Ethyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

2-(Morpholine-4-yl)ethyl 5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

Sodium (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

(5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy) acetic acid,

Methyl[5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,

Ethyl [5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,

2-(Morpholine-4-yl)ethyl 5 -aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

Sodium[5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,

(5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,

Methyl(5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

Ethyl(5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo [1,2-b]pyridazine-4-yloxy)acetate,

2-(Morpholine-4-yl)ethyl 5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,

Sodium (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, and

(5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo [1,2-b]pyridazine-4-yloxy) acetic acid,

and the prodrugs thereof; or their pharmaceutically acceptable salts; their parent acids; or their solvates.

xv) A pharmaceutical composition containing as active ingredient a compound as described in any one of i) to xiv).

xvi) A pharmaceutical composition as described in xv), which is for inhibiting sPLA₂.

xvii) A pharmaceutical composition as described in xv), which is for treatment or prevention of Inflammatory Diseases.

xviii) A method of inhibiting sPLA₂ mediated release of fatty acid which comprises contacting sPLA₂ with a therapeutically effective amount of a pyrrolo[1,2-b]pyridazine compound as described in i).

xix) A method of treating a mammal, including a human, to alleviate the pathological effects of Inflammatory Diseases; wherein the method comprises administration to said mammal of a pyrrolo[1,2-b]pyridazine compound as described in i).

xx) A compound as described in i) or a pharmaceutical formulation containing an effective amount of a pyrrolo[1,2-b]pyridazine compound as described in i) for use in treatment of Inflammatory Diseases.

xxi) A compound as described in i) or a pharmaceutical formulation containing an effective amount of a pyrrolo[1,2-b]pyridazine compound as described in i) for use as an inhibitor for inhibiting sPLA₂ mediated release of fatty acid.

xxii) A pyrrolo[1,2-b]pyridazine sPLA₂ inhibitor substantially as hereinbefore described with reference to any of the Examples.

xxiii) A compound represented by the formula (XII):

wherein R⁷ is —(CH₂)m—R¹² wherein m is an integer from 1 to 6, and R¹² is (d) a group represented by the formula:

wherein a, c, e, n, q, and t are independently an integer from 0 to 2, R¹³ and R¹⁴ are independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heteroaryl, and C1 to C10 haloalkyl, a is an oxygen atom or a sulfur atom, L⁵ is —(CH₂)v—, —C═C—, —C≡C—, —O—, or —S—, v is an integer from 0 to 2, β is —CH₂— or —(CH₂)₂—, γ is an oxygen atom or a sulfur atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, g is an integer from 0 to 2, r is an integer from 0 to 7, and u is an integer from 0 to 4, or is (e) a member of (d) substituted with at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 haloalkyloxy, C1 to C6 haloalkyl, aryl, and a halogen; and

R¹ is C1 to C3 alkyl, C2 to C3 alkenyl, C3 to C4 cycloalkyl, C3 to C4 cycloalkenyl, C1 to C2 haloalkyl, C1 to C3 alkyloxy, or C1 to C3 alkylthio.

In the present specification, the term “alkyl” employed alone or in combination with other terms means a straight- or branched chain monovalent hydrocarbon group having a specified number of carbon atoms. An example of the alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tridecanyl, n-tetradecanyl, n-pentadecanyl, n-hexadecanyl, n-heptadecanyl, n-octadecanyl, n-nonadecanyl, n-eicosanyl and the like.

The term “alkenyl” employed alone or in combination with other terms in the present specification means a straight- or branched chain monovalent hydrocarbon group having a specified number of carbon atoms and at least one double bond. An example of the alkenyl includes vinyl, allyl, propenyl, crotonyl, isopentenyl, a variety of butenyl isomers and the like.

The term “alkynyl” used in the present specification means a straight or branched chain monovalent hydrocarbon group having a specified number of carbon atoms and at least one triple bond. The alkynyl may contain (a) double bond(s). An example of the alkynyl includes ethynyl, propynyl, 6-heptynyl, 7-octynyl, 8-nonynyl and the like.

The term “carbocyclic group” used in the present specification means a group derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered, preferably 5 to 10 membered, and more preferably 5 to 7 membered organic nucleus whose ring forming atoms (other than hydrogen atoms) are solely carbon atoms. A group containing two to three of the carbocyclic group is also included in the above stated group. An example of typical carbocyclic groups includes (f) cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); cycloalkenyl (such as cyclobutylenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooptenyl); phenyl, spiro[5,5]undecanyl, naphthyl, norbornyl, bicycloheptadienyl, tolyl, xylyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenylcyclohexenyl, acenaphthyl, anthoryl, biphenylyl, bibenzylyl, and a phenylalkylphenyl derivative represented by the formula:

wherein x is an integer from 1 to 8.

The term “spiro[5,5]undecanyl” refers to the group represented by the formula:

Phenyl, cyclohexyl or the like is preferred as a carbocyclic groups in the R⁴ and R⁵.

The term “heterocyclic group” used in the present specification means a group derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nucleus having 5 to 14 ring atoms and containing 1 to 3 hetero atoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom. An example of the heterocyclic group includes pyridyl, pyrrolyl, pyrrolidinyl, piperidinyl, furyl, benzofuryl, thienyl, benzothienyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, indazolyl, imidazo[1,2-a]pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, puridinyl, dipyridinyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, morpholino, thiomorpholino, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, oxacanyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,4-thioxanyl, azetidinyl, hexamethyleneiminium, heptamethyleneiminium, piperazinyl and the like.

Furyl, thienyl or the like is preferred as a heterocyclic group in the R⁴ and R⁵.

Preferred carbocyclic and heterocyclic groups in R¹ are (g) a group represented by the formula:

wherein R¹³ and R¹⁴ are independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heteroaryl, and C1 to C10 haloalkyl, α is an oxygen atom or a sulfur atom, L⁵ is —(CH₂)v—, —C═C—, —C≡C—, —O—, or —S—, v is an integer from 0 to 2; β is —CH₂— or —(CH₂)₂—; γ is an oxygen atom or a sulfur atom; b is an integer from 0 to 3, d is an integer from 0 to 4; f, p, and w are an integer from 0 to 5; r is an integer from 0 to 7, and u is an integer from 0 to 4. When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R¹³ or R¹⁴ may be different from one another. When R¹³ is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group. A more preferable example includes (h) a group represented by the formula:

wherein R¹³, R¹⁴, α, β, and γ are the same as defined above, L⁶ is —CH₂—, —C═C—, —C≡C—, —O—, or —S—, and y is 0 or 1. When R¹³ is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group.

The “pyrrolo[1,2-b]pyridazine nucleus” is represented by the following structural formula together its numerical ring position for substituent placement:

The term “non-interfering substituent” in the present specification means C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C7 to C12 aralkyl (such as benzyl and phenethyl), C7 to C12 alkaryl, C2 to C8 alkenyloxy, C2 to C8 alkynyloxy, C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenylyl, C1 to C8 alkyloxy, C2 to C12 alkyloxyalkyl (such as methyloxymethyl, ethyloxymethyl, methyloxyethyl, and ethyloxyethyl), C2 to C12 alkyloxyalkyloxy (such as methyloxymethyloxy and methyloxyethyloxy), C2 to C12 alkylcarbonyl (such as methycarbonyl and ethylcarbonyl), C2 to C12 alkycarbonylamino (such as methylcarbonylamino and ethylcarbonylamino), C2 to C12 alkyloxyamino (such as methyloxyamino and ethyloxyamino), C2 to C12 alkyloxyaminocarbonyl (such as methyloxyaminocarbonyl and ethyloxyaminocarbonyl), C1 to C12 alkylamino (such as methylamino, ethylamino, dimethylamino, and ethylmethylamino), C1 to C6 alkylthio, C2 to C12 alkylthiocarbonyl (such as methylthiocarbonyl and ethyltiocarbonyl), C1 to C8 alkylsulfinyl (such as methylsulfinyl and ethylsulfinyl), C1 to C8 alkylsulfonyl (such as methylsulfonyl and ethylsulfonyl), C2 to c8 haloalkyloxy (such as 2-chloroethyloxy and 2-bromoethyloxy), C1 to C8 haloalkysulfonyl (such as chloromethylsulfonyl and bromomethylsulfonyl), C2 to C8 haloalkyl, C1 to C8 hydroxyalkyl (such as hydroxymethyl and hydroxyethyl), —C(O)O(C1 to C8 alkyl) (such as methyloxycarbonyl and ethyloxycarbonyl, —(CH₂)z—O—(C1 to C8 alkyl), benzyloxy, aryloxy (such as phenyloxy), arylthio (such as phenylthio), —(CONHSO₂R²⁵), —CHO, amino, amidino, halogen, carbamyl, carboxyl, carbalkyloxy, —(CH₂)z—COOH (such as carboxymethyl, carboxyethyl, and carboxypropyl), cyano, cyanoguanidino, guanidino, hydrazido, hydroxy, hydroxyamino, nitro, phosphono, —SO₃H, carbocyclic groups, heterocyclic groups wherein z is an integer from 1 to 8 and R²⁵ is C1 to C6 alkyl or aryl. These groups may be substituted by at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkyloxy, C2 to C6 haloalkyloxy, C1 to C6 haloalkyl, and halogens.

Preferable are halogens, C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, and C1 to C6 haloalkyl as the “non-interfering substituent” in the R¹. More preferable are halogens, C1 to C3 alkyl, C1 to C3 alkyloxy, C1 to C3 alkylthio, and C1 to C3 haloalkyl.

Preferable are (i) C1 to C6 alkyl, aralkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, C1 to C6 hydroxyalkyl, C2 to C6 haloalkyloxy, halogens, carboxy, C1 to C6 alkyloxycarbonyl, aryloxy, arylthio, carbocyclic groups, and heterocyclic groups as the “non-interfering substituents” in the R⁴, R⁵, R¹⁰, and R¹¹. More preferable are (j) C1 to C6 alkyl, aralkyl, carboxy, C1 to C6 hydroxyalkyl, phenyl, and C1 to C6 alkyloxycarbonyl.

The term “halogen” in the present specification means fluorine, chlorine, bromine, and iodine.

The term “cycloalkyl” in the present specification means a monovalent cyclic hydrocarbon group having a specified number of carbon atoms. An example of the cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The term “cycloalkenyl” in the present specification means a monovalent cyclic hydrocarbon group having a specified number of carbon atoms and at least one double bond(s). An example of the cycloalkenyl includes 1-cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl, 2-cyclobutenyl and the like.

In the present specification, an example of “alkyloxy” includes methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, n-pentyloxy, n-hexyloxy and the like.

In the present specification, an example of “alkylthio” includes methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, n-pentylthio, n-hexylthio and the like.

The term “acidic group” in the present specification means an organic group functioning as a proton donor capable of hydrogen bonding when attached to a pyrrolo[1,2-b]pyridazine nucleus through a suitable linking atom (hereinafter defined as “acid linker”). An example of the acidic group includes (k) a group represented by the formula:

wherein R¹⁸ is hydrogen atom, a metal, or C1 to C10 alkyl and each R¹⁹is independently hydrogen atom or C1 to C10 alkyl. Preferable is (1) —COOH, —SO₃H, or P(O)(OH)₂. More preferable is (m)—COOH.

The term “acid linker” in the present specification means a divalent linking group represented by a symbol —(L²)—, and it functions to join 4-position of pyrrolo[1,2-b]pyridazine nucleus to an “acidic group” in the general relationship. An example of it includes (n) a group represented by the formula:

M is —CH₂—, —O—, —N(R²⁴)—, or —S—, and R¹⁶ and R¹⁷ are independently hydrogen atom, C1 to C10 alkyl, aryl, aralkyl, carboxy, or halogens. Preferable are (o) —O—CH₂—, —S—CH₂—, —N(R²⁴)—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—, or —O—CH((CH₂)₂Ph)— wherein R²⁴ is hydrogen atom or C1 to C6 alkyl and Ph is phenyl. More preferable is (p) —O—CH₂— or —S—CH₂—.

In the present specification, the term “acid linker length” means the number of atoms (except for hydrogen atoms) in the shortest chain of a linking group —(L²)— which connects 4-position in pyrrolo[1,2-b]pyridazine nucleus with the “acidic group”. The presence of a carbocyclic ring in (L² counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a benzene and cyclohexane ring in the acid linker counts as two atoms in culculating the length of —(L²)—. preferable length is 2 to 3.

A symbol k in the formula (IV) is preferably 1.

The term “haloalkyl” in the present specification means the above described “alkyl” substituted with the above described “halogen” at arbitrary position(s). An example of the haloalkyl includes chloromethyl, trifluoromethyl, 2-chloromethyl, 2-bromomethyl and the like.

The term “hydroxyalkyl” in the present specification means the aforementioned “alkyl” substituted with hydroxy at arbitrary position(s). An example of the hydroxyalkyl includes hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like. In this case, hydroxymethyl is preferable.

In the present specification, the term “haloalkyl” in “haloalkyloxy” is the same as defined above. An example of it includes 2-chloroethyloxy, 2,2,2-trifluoroethyloxy, 2-chloroethyloxy and the like.

The term “aryl” in the present specification means a monocyclic or condensed cyclic aromatic hydrocarbon. An example of the aryl includes phenyl, 1 -naphthyl, 2-naphthyl, anthryl and the like. Particularly, phenyl and 1 -naphthyl are preferred. Such “aryl” is optionally substituted with C1 to C6 alkyl, hydroxy, C1 to C3 alkyloxy, halogen, nitro, substituted or unsubstituted amino, cyano, C1 to C3 haloalkyl, and the like at one or more position(s).

The term “aralkyl” in the present specification means a group wherein the aforementioned “alkl” is substituted with the above-mentioned “aryl”. Such aryl may have a bond at any substitutable position. An example of it includes benzyl, phenethyl, phenylpropyl (such as 3 -phenylpropyl), naphthylmethyl (such as 1-naphthylmethyl) and the like.

The term “group containing 1 to 4 non-hydrogen atoms” refers to relatively small groups which form substituents at the 6 position of the pyrrolo[1,2-b]pyridazine nucleus, said groups may contain non-hydrogen atoms alone, or non-hydrogen atoms plus hydrogen atoms as required to satisfy the unsubstituted valence of the non-hydrogen atoms, for example; (ii) groups absent hydrogen which contain no more than 4 non-hydrogen atoms such as —CF₃, —Cl, —Br, —NO₂, —CN, —SO₃; and (iii) groups having hydrogen atoms which contain less than 4 non-hydrogen atoms such as —CH₃, —C₂H₅, —CH═CH₂, —CH(CH₃)₂, and cyclopropyl.

An example of the “alkyloxycarbonyl” in the present specification includes methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl and the like.

The term “substituted amino” in the present specification includes amino substituted with C1 to C6 alkyl, aralkl, C1 to C6 alkylcarbonyl, C1 to C6 alkyloxycarbonyl, and the like at one or two position(s).

Preferred embodiments of the R⁷ of the formula (XXII) are C5 to C8 cycloalkylmethyl and phenylmethyl which is optionally substituted with halogen, C1 to C6 alkyl, aryl, alkyloxy, or aryloxy.

Preferable is C1 to C6 alkyl as the R⁸ of the formula (XXII).

A group of preferable substituents as the R¹ to R⁵ and the R^(A) of the compound represented by the formula (I) will be shown in items (A) to (W). Items (f) to (m) are the same group as described above.

As the R¹, (A): —(L¹)—R⁶, (B): —(CH₂)₁₋₂-(f), (C): —(CH₂)₁₋₂-(g), and (D): —(CH₂)₁₋₂-(h) are preferred.

As the R², (E): hydrogen atom, halogen, C1 to C3 alkyl, C3 to C4 cycloalkyl, or C1 to C3 alkyloxy; and (F): C1 to C3 alkyl or C3 to C4 cycloalkyl are preferred.

As the R^(A), (G): —C(═O)—C(═O)—NH₂, —CH₂C(═O)—NH₂, or —CH₂C(═O)—NHNH₂; and (H): —C(═O)—C(═O)—NH₂ are preferred.

As the R³, (I): -(n)-(k), (J): -(n)-(l), (K): -(n)-(m), (L): -(o)-(k), (M): -(o)-(l), (N): -(o)-(m), (O): -(p)-(k), (P): -(p)-(l), and (Q): -(p)-(m) are preferred.

As the R⁴, (R): hydrogen atom or non-interfering substituent, (S): hydrogen atom or (i), and (T): hydrogen atom or (j) are preferred.

As the R⁵, (U): hydrogen atom or (i), (V): hydrogen atom or (j), and (W): hydrogen atom are preferred.

A preferred group of compounds represented by the formula (I) is shown below.

(R¹,R²,R^(A),R⁴,R⁵)=(A,E,G,R,U), (A,E,G,R,V), (A,E,G,R,W), (A,E,G,S,U), (A,E,G,S,V), (A,E,G,S,W), (A,E,G,T,U), (A,E,G,T,V), (A,E,G,T,W), (A,E,H,R,U), (A,E,H,R,V), (A,E,H,R,W), (A,E,H,S,U), (A,E,H,S,V), (A,E,H,S,W), (A,E,H,T,U), (A,E,H,T,V), (A,E,H,T,W), (A,F,G,R,U), (A,F,G,R,V), (A,F,G,R,W), (A,F,G,S,U), (A,F,G,S,V), (A,F,G,S,W), (A,F,G,T,U), (A,F,G,T,V), (A,F,G,T,W), (A,F,H,U), (A,F,H,R,V), (A,F,H,R,W), (A,F,H,S,U), (A,F,H,S,V), (A,F,H,S,W), (A,F,H,T,U), (A,F,H,T,V), (A,F,H,T,W), (B,E,G,R,U), (B,E,G,R,V), (B,E,G,R,W), (B,E,G,S,U), (B,E,G,S,V), (B,E,G,S,W), (B,E,G,T,U), (B,E,G,T,V), (B,E,G,T,W), (B,E,H,R,U), (B,E,H,R,V), (B,E,H,R,W), (B,E,H,S,U), (B,E,H,S,V), (B,E,H,S,W), (B,E,H,T,U), (B,E,H,T,V), (B,E,H,W), (B,F,G,R,U), (B,F,G,R,V), (B,F,G,R,W), (B,F,G,S,U), (B,F,G,S,V), (B,F,G,S,W), (B,F,G,T,U), (B,F,G,T,V), (B,F,G,T,W), (B,F,H,R,U), (B,F,H,R,V), (B,F,H,R,W), (B,F,KS,U), (B,F,H,S,V), (B,F,H,S,W), (B,F,H,T,U), (B,F,H,T,V), (B,F,H,T,W), (C,E,G,R,U), (C,E,G,R,V), (C,E,G,R,W), (C,E,G,S,U), (C,E,G,S,V), (C,E,G,S,W), (C,E,G,T,U), (C,E,G,T,V), (C,E,G,T,W), (C,E,H,R,U), (C,E,H,R,V), (C,E,H,R,W), (C,E,H,S,U), (C,E,H,S,V), (C,E,H,S,W), (C,E,H,T,U), (C,E,H,T,V), (C,E,H,T,W), (C,F,G,R,U), (C,F,G,R,V), (C,F,G,R,W), (C,F,G,S,U), (C,F,G,S,V), (C,F,G,S,W), (C,F,G,T,U), (C,F,G,T,V), (C,F,G,T,W), (C,F,H,R,U), (C,F,H,R,V), (C,F,H,R,W), (C,F,H,S,U), (C,F,H,S,V), (C,F,H,S,W), (C,F,H,T,U), (C,F,H,T,V), (C,F,H,T,W), (D,E,G,R,U), (D,E,G,R,V), (D,E,G,R,W), (D,E,G,S,U), (D,E,G,S,V), (D,E,G,S,W), (D,E,G,T,U), (D,E,G,T,V), (D,E,G,T,W), (D,E,H,R,U), (D,E,H,R,V), (D,E,H,R,W), (D,E,H,S,U), (D,E,H,S,V), (D,E,H,S,W), (D,E,H,T,U), (D,E,H,T,V), (D,E,H,T,W), (D,F,G,R,U), (D,F,G,R,V), (D,F,G,R,W), (D,F,G,S,U), (D,F,G,S,V), (D,F,G,S,W), (D,F,G,T,U), (D,F,G,T,V), (D,F,G,T,W), (D,F,H,R,U), (D,F,H,R,V), (D,F,H,R,W), (D,F,H,S,U), (D,F,H,S,V), (D,F,H,S,W), (D,F,H,T,U), (D,F,H,T,V), and (D,F,H,T,W).

Preferred embodiments of this invention are compounds wherein R³ is any one of (I) to (Q) and (R¹,R²,R^(A),R⁴,R⁵) is any one of the above combinations.

The term, “Inflammatory Diseases” refers to diseases such as inflammatory bowel disease, sepsis, septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, chronic rheumatism, arterial sclerosis, cereberal hemorrhage, cerebral infarction, cardiac failure, cardiac infarction, psoriasis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, spondylarthropathris, ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, enterapathric spondylitis, Juvenile arthropathy or juvenile ankylosing spondylitis, Reactive arthropathy, infectious or post-infectious arthritis, gonoccocal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with “vasculitic syndromes”, polyarteritis nodosa, hypersensitivity vasculitis, Luegenec's granulomatosis, polymyalgin rheumatica, joint cell arteritis, calcium crystal deposition arthropathris, pseudo gout, non-articular rheumatism, bursitis, tenosynomitis, epicondylitis (tennis elbow), carpal tunnel syndrome, repetitive use injury (typing), miscellaneous forms of arthritis, neuropathic joint disease (charco and joint), hemarthrosis (hemarthrosic), Henoch-Schonlein Purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis associated with certain diseases, surcoilosis, hemochromatosis, sickle cell disease and other hemoglobinopathries, hyperlipoproteineimia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat's Disease, systemic lupus erythrematosis, or relapsing polychondritis and related diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula I in an amount sufficient to inhibit sPLA₂ mediated release of fatty acid and to thereby inhibit or prevent the arachidonic acid cascade and its deleterious products.

The terms, “mammal” and “mammalian” include human.

The term “solvate” includes, for example, solvates with organic solvents, hydrates, and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

The compounds of the invention represented by the formula (I) can be synthesized in accordance with the following method A. The compound (XV) in the method A can be also synthesized in accordance with the following method B.

(Method A)

wherein R¹, R², R⁴, R⁵, X, and Y are as defined above; R²⁶ is an acidic group.

(Step 1)

To a solution of the compound (VI) which is commercially available or is synthesized in accordance with well-known method in a solvent such as tetrahydrofuran, diethyl ether, and ethylene glycol dimethyl ether is added a base such as lithium diisopropyl amide and n-butyllithium at −78° C., to −20° C., preferably −78° C. to −60° C. To the reaction mixture is added alkenyl halide such as allyl bromide and allyl chloride at the same temperature and the resulting mixture is stirred for 1 to 24 h, preferably 1 to 8 h. After the reaction mixture is subjected to a usual work-up, the compound (VII) can be obtained (see J. Chem. Soc. Parkin. Trans.1, 1987, 1986).

(Step 2)

To a solution of the compound (VII) in a solvent such as tetrahydrofuran, diethyl ether, and ethylene glycol dimethyl ether is added Grignard reagent (R¹MgHal: Hal is a halogen) at −20° C. to 0° C., preferably −15° C. to −10° C. and the resulting mixture is stirred for 1 to 15 h, preferably 1 to 8 h at −20° C. to 30° C., preferably 0° C. to 25° C. After the reaction mixture is subjected to a usual work-up, the compound (VIII) can be obtained (see Synthesis, 996, 1988).

(Step 3)

The present step includes ozone-oxidation of the double bond. A solution of the compound (VIII) in a solvent such as dichloromethane, ethyl acetate, and methanol is treated with ozone at −78° C. to 0° C., preferably −78° C. to −60° C. Without isolating the ozonide, the mixture is treated with a reducing agent such as dimethyl sulfide, triphenylphosphine, triethoxyphosphine, and zinc-acetic acid or hydrogen to give the aldehyde derivative (IX).

(Step 4)

To a solution of the compound (IX) in a solvent such as dioxane, tetrahydrofuran, and diethyl ether are added the compound (X) and an acid such as hydrochloric acid, sulfuric acid, and acetic acid. The resulting mixture is stirred for 0.5 to 3 h at 50° C. to 100° C. to give the pyrrole derivative (XI) which is protected by phthalimide at N-position (Chem. Ber., 102, 3268, 1969).

(Step 5)

The present step is the one for deprotecting the phthalimide group of the compound (XI). This step may be carried out in accordance with a usual deprotecting method as described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons). For example, to a solution of the compound (XI) in an alcohol solvent such as ethanol is added hydrazine and the resulting mixture is stirred for 0.5 to 3 h at 50° C. to 100° C. to give the amino derivative (XII).

(Step 6)

The present step is the one for alkylating the amino group. The compound (XII) and the compound (XIII) are reacted for 10 to 60 min at 100° C. to 150° C. to give the compound (XIV) (see J. Heterocyclic Chem., 31, 409, 1994).

(Step 7)

The present step is the one for constructing pyrrolo[1,2-b]pyridazine ring. The compound (XIV) is dissolved in a solvent such as Dowtherm-A and SAS-296 and the mixture is stirred for 1 to 8 h at 150° C. to 250° C. to give the pyrrolo[1,2-b]pyridazine derivative (XV) (see J. Heterocyclic Chem., 31, 409, 1994). The hydroxy group at 4-position is converted into halogen by the usual method, then the halogen is may be converted into a thiol group or the like.

(Step 8)

To a solution of the compound (XV) in a solution such as tetrahydrofuran and dimethylformamide are added a base such as potassium carbonate and sodium hydride and R²⁶-Hal (Hal is halogen) and the resulting mixture is stirred for 1 to 15 h at 0° C. to 100° C., preferably 20 to 40° C. to give the compound (XVI).

(Step 9)

The present step is the one for introducing a substituent to 5-position. The compound (XVI) is dissolved in a solvent such as 1,2-dichloroethane, tetrahydrofuran, and Hal-C(═X)—C(═X)-Hal (for example, oxalyl chloride) and a base such as N-methylmorpholine, triethylamine are added to the solution, and the mixture is stirred for 1 to 10 h, preferably 3 to 6 h at 30° C. to 70° C., preferably 40° C. to 60° C. The reaction mixture is poured into cold aqueous ammonia, and the resulting mixture is stirred for 5 to 30 minutes, preferably 10 to 20 minutes. After the reaction mixture is subjected to an ordinary work-up, the compound (XVII) can be obtained.

(Method B)

wherein R¹, R², R⁴, and R⁵ are as defined above, R²⁷ is C1 to C3 alkyl, R²⁸ is lower alkyl R²⁸ with the adjacent oxygen may form a 1,3-dioxolane ring, and R²⁹ is a phthalimido or NHCO₂Et.

(Step 1)

To a solution of the compound (XVIII) in a solvent such as dimethylformamide are added a halogenated alkyl derivative such as bromoacetaldehyde ethyleneacetal and a base such as potassium carbonate, potassium t-butoxide, and sodium hydride and the resulting mixture is stirred for 3 to 80 h, preferably 5 to 7 h at room temperature to 180° C., preferably 20 to 150° C. to give the compound (XIX).

(Step 2)

To a solution of the compound (XIX) in a solvent such as dimethylsulfoxide is added a reagent such as potassium acetate and sodium acetate and the resulting mixture is stirred for 1 to 20 h, preferably 3 to 15 h at 20° C. to 200° C., preferably 100° C. to 180° C. to give the compound (XX).

(Step 3)

To a solution of Grignard reagent (R¹MgHal, Hal is halogen) or R¹Li in a solvent such as ether, tetrahydrofuran, and dimethoxyethane is added a solution of the compound (XX) in ether, tetrahydrofuran, and dimethoxyethane and the resulting mixture is stirred for 1 to 48 h, preferably 2 to 24 h at 0° C. to 70° C., preferably 20 to 60° C. to give the compound (XXI).

(Step 4)

To a solution of the compound (XXI) in a solvent such as ethanol, methanol, dioxane, and tetrahydrofuran are added N-aminophthalimide (compound (X)) or ethyl carbazate (compound (XXII)) and an acid such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid and the resulting mixture is stirred for 5 min to 2 h, preferably 10 min to 1 h at 20° C. to 120° C., preferably 50 to 100° C. to give the compound (XXIII).

(Step 5)

The present step may be carried out in accordance with the same procedure as that of the method A—step 5.

To a solution of the compound (XII′) in a solvent such as chloroform, dichloroethane, tetrahydrofuran, and toluene are added β-ketoester such as acetoacetic acid methylester and an acid catalyst such as p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, trifluoroacetic acid and the resulting mixture is stirred for 1 to 20 h, preferably 3 to 15 h to give the compound (XV). The generated water in situ is dehydrated by a Dean-Stark apparatus with molecular sieve 4A or the like.

(Method C)

wherein R¹, R², R⁴, R²⁶, X, and Y are as defined above, Hal is halogen, R³⁰ is —OR³¹, —SR³¹, —NHR³¹, —N(R³¹)₂, —CN, —N₃, or the like wherein R³¹ is independently alkyl, aryl, or the like.

(Step 1)

The compound (XVI′) is obtained in a manner similar to that described in the method A—step 8.

(Step 2)

The compound (XVI′) is dissolved in a solvent such as dimethylformamide, acetonitrile, acetone, dimethylsulfoxide, methanol, ethanol, isopropanol and to the solution is added a base as a dehydrohalogenating agent such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium acetate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium t-butoxide. Then to the mixture is added a reagent such as R³¹OH, R³¹SH, R³¹NH₂, (R³¹)₂NH and the resulting mixture is stirred for 1 to 48 h preferably 1 to 24 h at −20° C. to 100° C., preferably 0° C. to 80° C. to give the compound (XXIV).

(Step 3)

The compound (XVII′) is obtained in a manner similar to that described in the method A—step 9.

(Method D)

wherein R¹, R²,R⁴, R²⁶, R³⁰, X, Y, and Hal are as defined above.

(Step 1)

The compound (XXV) is obtained in a manner similar to that described in the method A—step 9.

The compound (XVII′) is obtained in a manner similar to that described in the method C—step 2.

Where a compound of the present invention has an acidic or basic functional group, a variety of salts each having higher water solubility and more physiologically suitable properties than those of the original compound can be formed. An example of typical pharmaceutically acceptable salts includes salts with alkali metal and alkaline earth metal such as lithium, sodium, potassium, magnesium, aluminum and the like, but it is to be noted that such pharmaceutically acceptable salts are not limited thereto. A salt is easily manufactured from a free acid by either treating an acid in a solution with a base, or allowing an acid to be in contact with an ion exchange resin. Addition salts of the compounds according to the present invention with relatively non-toxic inorganic bases and organic bases, for example, amine cation, ammonium, and quaternary ammonium derived from nitrogenous bases having a basicity sufficient for forming a salt of the compounds of the present invention are included in the definition of “pharmaceutically acceptable salts”. (e.g., S. M. Berge et al., “Pharmaceutical Salts,” J. Phar. Sci., 66, 1-19 (1977)) Furthermore, basic groups of a compound according to the present invention are reacted with a suitable organic or inorganic acid to form salts such as acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartarate, borates, bromides, camcyrates, carbonates, chlorides, clubranates, citrates, edetates, edicirates, estrates, ethylates, fluorides, fumarates, gluseptates, gluconates, glutamates, glycolialsanyrates, hexyliresorcinates, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, laurates, malates, malseates, manderates, mesylates, methylbromides, methylnitrates, methylsulfates, mucates, napcylates, nitrates, oleates, oxarates, palmitates, pantothenates, phosphates, polygalacturonates, salicirates, stearates, subacetates, sucinates, tanates, tartrates, tosylates, trifluoroacetates, trifluoromethanesulfonates, valerates and the like. In case of forming a hydrate, a questioned compound may be coordinated with a suitable number of water molecules.

In the case where a compound of the present invention has one or more of chiral center(s), it may exist as an optically active member. Likewise, in the case where a compound contains alkenyl or alkenylene, there is a possibility of cis- and trans-isomers. Mixtures of R- and S-isomers as well as of cis- and trans-isomers, and mixtures of R- and S-isomers containing racemic mixture are included in the scope of the present invention. Asymmetric carbon atom may exist also in a substituent such as alkyl group. All such isomers are included in the present invention together with these mixtures. In the case where a specified streoisomer is desired, either it is manufactured by applying a manner which has been well known by those skilled in the art wherein a starting material having an asymmetrical center which has been previously separated is subjected to stereospecific reaction to the starting material, or it is manufactured by preparing a mixture of stereoisomers, and thereafter separating the mixture in accordance with a well-known manner.

Prodrug is a derivative of the compound having a group which can be decomposed chemically or metabolically, and such prodrug is a compound according to the present invention which becomes pharmaceutically active by means of solvolysis or by placing the compound in vivo under a physiological condition. Although a derivative of the compounds according to the present invention exhibits activity in both forms of acid derivative and basic derivative, acid derivative is more advantageous in solubility, tissue affinity, and release control in mammal organism (Bungard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam, 1985). Ester prodrugs are well known (see, Silverman, Richard B, The Organic Chemistry of Drug Design and Drug Action, Chapter 8, New York, N.Y. Academic Press, ISBN 0-12-643730-0) and are a preferred prodrug form for the compounds of this invention and also for prodrugs used in the method of treating Inflammatory Disease as taught herein. For instance, prodrugs each containing an acid derivative such as an ester which is prepared by reacting a basal acid compound with a suitable alcohol, or an amide which is prepared by reacting a basal acid compound with a suitable amine are well known by those skilled in the art. Simple aliphatic or aromatic esters derived from acid groups contained in the compounds according to the present invention are preferable prodrugs. Particularly preferred esters as prodrugs are methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, morpholinoethyl ester, and N,N-diethylglycolamido ester.

Methyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a solvent such as dimethylformamide) with iodo methane (available from Aldrich Chemical Co., Milwaukee, Wis. USA; Item No. 28,956-6).

Ethyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a solvent such as dimethylformamide) with iodo ethane (available from Aldrich Chemical Co., Milwaukee, Wis. USA; Item No. I-778-0).

N,N-diethylglycolamido ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with 2-chloro-N,N-diethylacetamide (available from Aldrich Chemical Co., Milwaukee, Wis. USA; Item No. 25,099-6).

Morpholinylethyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with 4-(2-chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4,220-3).

Double ester such as (acyloxy)alkyl ester or ((alkyloxycarbonyl)oxy)alkyl ester type prodrugs may be optionally manufactured.

The term “inhibit” means that release of fatty acid started by sPLA₂ decreases significantly by the compounds of the present invention from viewpoint of prevention and treatment of disease. The term “pharmaceutically acceptable” means that carriers, diluents, or additives are compatible with other ingredients in a formulation and are not harmful for recipients.

The compounds of the present invention exhibit sPLA₂ inhibiting activity as per the description of the experimental examples which will be described hereinafter. Accordingly, when a curatively effective amount of the compounds represented by the formulae (I), (II), (III), and (IV), the prodrug derivatives thereof, or their pharmaceutically acceptable salts, or their solvates is administered to any of mammals (including human being), it functions effectively as a curative medicine for diseases of septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arterial sclerosis, cerebral hemorrhage, cerebral infarction, inflammatory colitis, mange, cardiac failure, cardiac infarction.

The compounds of the present invention may be administered to a patient through a variety of routes including oral, aerosol, rectal, percutaneous, subcutaneous, intravenous, intramuscular, and nasal routes. A formulation according to the present invention may be manufactured by combining (for example, admixing) a curatively effective amount of a compound of the present invention with a pharmaceutically acceptable carrier or diluent. The formulation of the present invention may be manufactured with the use of well-known and easily available ingredients in accordance with a known method.

In case of manufacturing a composition according to the present invention, either active ingredients are admixed with a carrier, or they are diluted with a carrier, or they are contained in a carrier in the form of capsule, sacheier, paper, or another container. In case of functioning a carrier as a diluent, the carrier is a solid, semi-solid, or liquid material which functions as a medium. Accordingly, a formulation according to the present invention may be produced in the form of tablet, pill, powder medicine, intraoral medicine, elixir agent, suspending agent, emulsifier, dissolving agent, syrup agent, aerosol agent (solid in liquid medium), and ointment. Such a formulation may contain up to 10% of an active compound. It is preferred to prepare a compound according to the present invention prior to administration.

Any suitable carrier which has been well known by those skilled in the art may be used for the formulation. In such formulation, a carrier is in the form of solid, liquid, or a mixture of solid and liquid. For instance, a compound of the present invention is dissolved into 4% dextrose/0.5% sodium citrate aqueous solution so as to be 2 mg/ml concentration for intravenous injection. Solid formulation includes powder, tablet, and capsule. Solid carrier consists of one or more of material(s) for serving also as fragrant, lubricant, dissolving agent, suspension, binder, tablet disintegrator, capsule. A tablet for oral administration contains a suitable excipient such as calcium carbonate, sodium carbonate, lactose, calcium phosphate and the like together with a disintegrator such as corn starch, alginic acid and the like and/or a binder such as gelatin, acacia and the like, and a lubricant such as magnesium stearate, stearic acid, talc and the like.

In a powder medicine, a carrier is a finely pulverized solid which is blended with finely pulverized active ingredients. In a tablet, active ingredients are admixed with a carrier having required binding power in a suitable ratio, and it is solidified in a desired shape and size. Powder medicine and tablet contain about 1 to about 99% by weight of the active ingredients being novel compounds according to the present invention. An example of suitable solid carriers includes magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methyl cellulose, sodium carboxymethylcellulose, low-melting wax, and cocoa butter.

An axenic liquid formulation contains suspending agent, emulsifier, syrup agent, and elixir agent. Active ingredients may be dissolved or suspended into a pharmaceutically acceptable carrier such as sterile water, a sterile organic solvent, a mixture thereof and the like. Active ingredients may be dissolved frequently into a suitable organic solvent such as propylene glycol aqueous solution. When finely pulverized active ingredients are dispersed into aqueous starch, sodium carboxylmethylcellulose solution, or suitable oil, the other compositions can be prepared.

A lyophilized preparation may be prepared by dissolving active ingredients in a solution such as water, if necessary, with a solubilizer such as citric acid, edetic acid, polyphosphoric acid and their salts and a stabilizer such as mannitol, xylitol, sorbitol, glucose, fructose, lactose and maltose and lyophilizing it.

The method of the invention for inhibiting sPLA₂ mediated release of fatty acids comprises contacting mammalian sPLA₂ with a therapeutically effective amount of a pyrrolo[1,2-b]pyridazine sPLA₂ inhibitors (and formulation containing such inhibitors) as taught, supra.

Preferably compounds of the invention (per Formula (I) or (II) or (III) or (IV) or pharmaceutical formulations containing these compounds) are in unit dosage form for administration to a mammal. The unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these. The quantity of Active ingredient in a unit dose of composition may be varied or adjusted from about 0.1 to about I 000 milligrams or more according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration.

The improved method of treatment for sepsis using the pyrrolo[1,2-b]pyridazine sPLA₂ inhibitors (and formulation containing such inhibitors) may be practiced as follows:

The inhibitors of this invention are given by injection, either subcutaneously or into muscle tissue or by injection into a vein. Intravenous injection is the preferred mode of delivery to the mammal being treated and offers the advantage of a quick effect and rapid access into the circulation system, particularly in emergency situations.

It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration and the condition being treated. Typical daily doses will contain a non-toxic Compound (I) dosage level of from about 0.01 mg/kg to about 50 mg/kg of body weight of an Active ingredient of this invention.

This invention is a method of treating or preventing Inflammatory diseased, (e.g., sepsis, rheumatoid arthritis, osteoarthritis, asthma) by administering to a mammal in need thereof a therapeutically effective amount inhibitor. The administration to a septic patient may be either continuous or intermittent.

The decision to begin the therapy for sepsis will be based upon the appearance of the clinical manifestations of sepsis or laboratory tests which show initiation of the sepsis cascade (inclusive of renal complications or coagulation abnormalities or multiple organ failure). Typical clinical manifestations are fever, chills, tachycardia, tachypnea, altered mental state, hypothermia, hyperthermia, accelerated or repressed breathing or heart rates, increased or decreased white blood cell count, and hypotension. These and other symptoms are well known in the art as set out in standard references such as, Harrison's Principles of Internal Medicine (ISBN 0-07-032370-4) 1994, pages 511-515.

The decision to determine the length of therapy may be supported by standard clinical laboratory results from commercially available assays or instrumentation supporting the eradication of the symptoms defining sepsis. The method of the invention may be practiced by continuously or intermittently administering a therapeutically effective dose of the inhibitor. The administration can be conducted for up to a total of about 60 days with a preferred course of therapy lasting for up to 10 days.

The decision to end therapy by the method of the invention may be supported by standard clinical laboratory results from commercially available assays or instrumentation or the disappearance of clinical symptoms characteristic of sepsis. The therapy may be restarted upon the return of sepsis. Pediatric forms of sepsis are also successfully treated by the methods, compounds, and formulations of this invention.

When the compound of the present invention is a crystallized, it may show various crystal forms and crystal habits.

The present invention will be described in more detail in conjunction with examples and test examples hereinafter, but it is to be noted that the present invention is not limited thereto.

In the examples, the following abbreviations are used.

Me: methyl

Et: ethyl

Pr: propyl

Ph: phenyl

NPhth: phthaloylimide

(d) of the melting point: decomposition temperature

DBU: 1,8-diazabicyclo[5.4.0]-7-undecene

EXAMPLE Example 1

Example 1—Step 1

The compound (1) (18.2 g, 0.160 mol) and 90% acetaldehyde (9.43 g, 0.190 mol) were dissolved in 20 ml of acetic acid and to the mixture were added 10% Pd—C catalyst (300 mg) and acetic acid solution (10 ml) of piperidine (0.63 ml, 6.37 mmol). The resulting mixture was stirred for 3 h at room temperature under hydrogen at 1 to 2 atm. The reaction mixture was filtered for removing the catalyst, diluted with toluene, and washed with water. The mixture was distilled under reduced pressure to give the compound (2) (20.00g, 88%, boiling point 92 to 94° C. (13 mmHg)) as colorless liquid (see OS, III, 385, 1955. J. Am. Chem. Soc., 66, 886 (1944)). OS, III, 385, 1955. J. Am. Chem. Soc., 66, 886 (1944)).

Example 1—Step 2

To a solution of the compound (2) (19.2 g, 0.140 mol) in acetone (200 ml) were added allyl bromide (60.2 ml, 0.700 mol) and potassium carbonate (36.0 g, 0.260 mol) and the resulting mixture was heated under reflux for 5 h. The reaction mixture was filtered and the filtrate was distilled under reduced pressure to give the compound (3) (22.0 g, 89%, boiling point 107 to 109° C. (14 mmHg)) as colorless liquid (see Compt. Rend., 253. 1808 (1961)).

Example 1—Step 3

The compound (3) (16.8 g, 92.5 mmol) and potassium acetate (10.0 g, 102 mmol) were dissolved in 85 ml of dimethylsulfoxide and the resulting mixture was stirred for 5 h at 150° C. To the reaction mixture was added water, the mixture was extracted with ether, and the organic layer was washed with water, dried over magnesium sulfate, and distilled at atmospheric to give the compound (4) (8.00 g, 79%, boiling point 168 to 172° C.) (see Compt. Rend., 253, 1808 (1961) and Indian J. Chem., 25, 1249 (1986))

Also, the compound (4) may be synthesized in accordance with the method described in J. Chem. Soc. Perkin Trans. 1, 1837, 1986. described in J. Chem. Soc. Perkin Trans. 1, 1837, 1986.

Example 1—Step 4

To a solution of magnesium (3.03 g, 0.125 mol) and 1,2-dibromoethane (0.49 ml, 5.67 mmol) in 70 ml of ether was added a solution of benzyl bromide (21.3 g, 0.125 mmol) in 30 ml of ether under ice-cooling. The mixture was allowed to warm to the room temperature and stirred until magnesium was dissolved. A solution of the compound (4) (12.4 g, 0.113 mol) in 30 ml of ether was added dropwise to the resulting mixture and the reaction mixture was heated under reflux for 2 h. To the reaction mixture was added water under ice-cooling and the mixture was acidified with 50 ml of 2.5 N sulfuric acid. The resulting mixture was stirred for 100 min on a water bath (90° C.) while removing ether. The reaction mixture was extracted with ether and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on silica gel using ethyl acetate-hexane (1:20) and appropriate fractions were distilled under reduced pressure to give the compound (5) (17.6 g, 77%, boiling point 90 to 91° C. (0.4 mmHg)) as colorless liquid (see Synthesis, 996, 1988).

¹H-NHR (CDCl₃): 0.81 (3H, t, J=7.4 Hz), 1.41-1.78 (2H, m), 2.09-2.41 (2H, 2.56-2.70 (1H, m), 3.71 (2H, s), 4.96-5.06 (2H, m), 5.56-5.77 (1H, m), 7.15-7.37 (5, m).

Example 1—Step 5

The compound (5) (13.4 g, 66.1 mmol) was dissolved in 150 ml of dichloromethane, ozone gas was introduced to the mixture at −78° C. until the starting material disappeared, and the excess amount of ozone gas was replaced by argon gas. To the resulting mixture was added a solution of triphenylphosphine (17.7 g, 67.4 mmol) in 50 ml of dichloromethane and the mixture was stirred for 30 min at room temperature. After the solvent was removed, precipitated crystals were filtered with washing with a mixed solvent of ethyl acetate and hexane and the filtrate was concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography and using ethyl acetate and hexane (1:4) as an eluent to give the compound (6) (11.2 g, 83%) as colorless liquid.

¹H-NHR (CDCl₃): 0.87 (3H, t, J=7.5 Hz), 1.41-1.75 (2H, m), 2.50 (1H, dd, J=18.3, 3.9 Hz), 2.96 (1H, dd, J=18.3, 9.6 Hz), 3.06-3.15 (1H, m), 3.84 (1H, d, J=16.2 Hz), 3.91 (1H, d, J=16.2 Hz), 7.20-7.36 (5H, m), 9.70 (1H, s).

Example 1—Step 6

The compound (6) (11.2 g, 54.6 mmol) and N-aminophthalimide (8.85 g, 54.6 mmol) were suspended in 250 ml of dioxane, 5N hydrochloric acid (6 ml, 30.0 mmol) was added to the suspension, and the mixture was stirred for 30 min at 100° C. The half of the reaction mixture was concentrated, diluted with ether, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and the fractions eluting with chloroform/hexane=2:1 were collected and recrystallized from hexane to give the compound (7) (14.8 g, 82%, melting point 153 to 154° C.) as colorless crystals (see Chem. Ber., 102, 3268(1969)).

Elemental Analysis C₂₁H₁₈N₂O₂; Calcd.: C, 76.34; H, 5.49; N, 8.48. Found.: C, 76.11; H, 5.47; N, 8.69. ¹H-NHR (CDCl₃): 1.22 (3H, t, J=7.5 Hz), 2.52 (2H, q, J=7.5 Hz), 3.81 (2H, s), 6.24 (1H, d, J=3.3 Hz), 6.60 (1H, d, J=3.3 Hz), 6.91-7.03 (5H, m), 7.74-7.83 (4H, m).

Example 1—Step 7

The compound (7) (14.9 g, 45.2 mmol) was suspended in 300 ml of ethanol, hydrazine monohydrate (5.5 ml, 113 mmol) was added to the suspension, and the mixture was stirred for 30 min at 100° C. The precipitated crystals were filtered off and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel using chloroform to give the compound (XII-1) (9.00 g, 99%) as colorless oil.

¹H-NHR (CDCl₃): 1.16 (3H, t, J=7.5 Hz), 2.46 (2H, q, J=7.5 Hz), 3.99 (2H, s), 4.23 (1H, br s), 5.94 (1H, d, J=2.7 Hz), 6.64 (1H, d, J=2.7 Hz), 7.07-7.30 (5H, m).

Example 1—Step 8

Diethyl ethoxymethylenemalonate (7.57 g, 35.0 mmol) was added to the compound (XII-1) (6.38 g, 31.9 mmol) and the mixture was heated for 40 min at 125° C. with removing ethanol generated in situ. To the reaction mixture was added hexane and the precipitated crystals were filtered to give the compound (8) (7.67 g, 65%, melting point 60 to 61° C.) as colorless crystals. The filtrate was purified by chromatography on silica gel (elution with ethyl acetate/hexane=1/6) to give the compound (8) (3.54 g, 30%) as colorless crystals (see J. Heterocyclic Chem., 31, 409, 1994).

Elemental Analysis C₂₁H₂₆N₂O₄, Calcd: C, 68.09; H, 7.07; N, 7.56. Found: C, 67.69; H, 7.06; N, 7.68. ¹H-NHR (CDCl₃): 1.20 (3H, t, J=7.2 Hz), 1.21 (3H, t, J=7.2 Hz), 1.33 (t, J=6.9 Hz), 2.51 (2H, q, J=6.9 Hz), 3.88 (2H, s), 4.08 (2H, q, J=7.2 Hz), 4.24 (2H, q, J=7.2 Hz), 6.07 (1H, d, J=3.3 Hz), 6.66 (1H, d, J=3.3 Hz), 7.00-7.28 (5H, m), 7.67 (1H, d, J=11.1 Hz), 10.32 (1H, d, J=11.1 Hz).

Example 1—Step 9

The compound (8) (11.9 g, 32.1 mmol) was dissolved in SAS-296 (phenylxylylethane) and the mixture was heated for 5 h at 200 to 210° C. under argon atmosphere. The reaction mixture was chromatographed on silica gel using toluene/hexane (=1/2) to give the compound (9) (6.85 g, 66%) as yellow crystals. The crystals were recrystallized from hexane (melting point 75 to 76° C.).

Elemental Analysis C₁₉H₂₀N₂O₃, Calcd.: C, 70.35; H, 6.21; N, 8.64. found.: C, 70.22; H, 6.28; N, 8.88. ¹H-NHR (CDCl₃): 1.24 (3H, t, J=7.5 Hz), 2.66 (2H, q, J=7.5 Hz), 4.37 (2H, s), 6.88 (1H, s), 7.12-7.25 (5H, m), 8.28 (1H, s), 12.18 (1H, s).

Example 1—Step 10

The compound (9) (3.02 g, 9.30 mmol) was dissolved in 10 ml of dimethylsulfoxide. Sodium chloride (598 mg, 10.2 mmol) and water (519 mg, 28.8 mmol) were added to the solution and the mixture was stirred for 4 h at 150° C. The solvent was removed and the residue was purified by chromatography on silica gel (elution with ethyl acetate/hexane=1/4) to give the compound (10) (1.32 g, 63%) as colorless crystals. This crystals were recrystallized from ether and hexane (melting point 113 to 114° C.).

Elemental Analysis C₁₆H₁₆N₂O, Calcd.: C, 76.16; H, 6.39; N, 11.10. Found: C, 75.93; H, 6.45; N, 11.27. ¹H-NHR (CDCl₃): 1.24 (3H, t, J=7.5 Hz), 2.68 (2H, q, J=7.5 Hz), 4.39 (2H, s), 5.58 (1H, d, J=5.4 Hz), 6.53 (1H, s), 7.12-7.25 (5H, m), 7.80 (1H, d, J=5.4 Hz).

Example 1—Step 11

The compound (10) (1.03 g, 4.10 mmol) was dissolved in 8 ml of tetrahydrofuran. Potassium carbonate (680 mg, 4.92 mmol) and a solution of methyl bromoacetate (753 mg, 4.92 mmol) in 2 ml of tetrahydrofuran were added to the solution and the mixture was heated for 3 h at 50° C. The reaction mixture was diluted with chloroform and filtered. The filtrate was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to silica gel column chromatography (eluting with toluene/ethyl acetate=1:50) to give the compound (11) (850 mg, 64%) as colorless crystals. This crystals were recrystallized from ether and methanol (melting point 94 to 95° C.).

Elemental Analysis C₁₉H₂₀N₂O₃, Calcd.: C, 70.35; H, 6.21; N, 8.64. Found: C, 70.32; H, 6.29; N, 8.88. ¹H-NHR (CDCl₃): 1.24(3H, t, J=7.5 Hz), 2.69 (2H, q, J=7.5 Hz), 3.82 (3H, s), 4.39 (2H, s), 4.78 (2H, s), 5.72 (1H, d, J=5.4 Hz), 6.63 (1H, s), 7.10-7.25 (5H, m), 7.84 (1H, d, J=5.4Hz).

Example 1—Step 12

To a solution of oxalyl chloride (752 mg, 5.92 mmol) in 7 ml of dichloromethane were added a solution of the compound (11) (384 mg, 1.18 mmol) in 3 ml of dichloromethane and N-methylmorpholine (240 mg, 2.37 mmol) at −15° C. and the mixture was stirred for 2 h at 0° C. After the mixture was added to an ice-cold aqueous ammonia stirred for 10 min at room temperature, the mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from methanol to give the compound (I-1) (416 mg, 89%, melting point 210 to 212° C.) as pale yellow crystals.

Elemental Analysis C₂₁H₂₁N₃O₅, Calcd.: C, 63.79; H, 5.35; N, 10.63. Found: C, 63.59; H, 5.39; N, 10.91. ¹H-NHR (CDCl₃): 1.16 (3H, t, J=7.5 Hz), 2.86 (2H, q, J=7.5 Hz), 3.80 (3H, s), 4.37 (2H, s), 4.76 (2H, s), 5.56 (1H, br. s), 6.06 (1H, d, J=5.4 Hz), 6.70 (1H, br s), 7.13-7.25 (5H, m), 8.02(1H, d, J=5.4Hz).

Example 1—Step 13

The compound (I-1) (248 mg, 0.627 mmol) was suspended in 3 ml of methanol, 1 ml of 1N sodium hydroxide was added to the suspension at room temperature, and the mixture was stirred for 1 h. The mixture was acidified with 1 N hydrochloric acid under ice-cooling and precipitated crystals were filtered to give the compound (I-2) (162 mg, 86%, decomposition point 252 to 255° C.) as pale yellow crystals.

Elemental Analysis C₂₀H₁₉N₃O₅, Calcd.: C, 62.99; H, 5.02; N, 11.02. Found: C, 62.80; H, 5.06; N, 11.21. ¹H-NHR (DMSO): 1.04 (3H, t, J=7.2 Hz), 2.79 (2H, q, J=7.2 Hz), 4.35 (2H, s), 4.88 (2H, s), 6.48 (1H, d, J=5.4 Hz), 7.12-7.29 (5H, m), 7.40 (1H, br s), 7.79 (1H, br. s), 8.23 (1H, d, J=5.4 Hz), 13.29 (1H, br s).

Example 1—Step 14

The compound (I-2) (51.4 mg, 0.134 mmol) was suspended in 2 ml of H₂O and 0.1 N sodium hydroxide (1.34 ml, 0.134 mmol) was added to the mixture under ice-cooling. The mixture was filtered and lyophilized to give the compound (I-3) (50.1 mg, decomposition point 280° C.) as yellow powder.

Example 2

(Step 1)

A mixture of the compound (XII-1) (601 mg, 3 mmol), methyl acetoacetate (348 mg, 3 mmol), p-toluenesulfonic acid monohydrate (29 mg, 0.15 mmol) and 20 ml of chloroform was heated under reflux for 15 h with an oil-bath. Generated water was dehydrated by a Dean-Stark apparatus with molecular sieve 4A. To the reaction mixture were added water and 25 mg of sodium bicarbonate. The mixture was extracted with chloroform, dried over magnesium sulfate, and subjected to silica gel column chromatography (16 g of silica gel, eluting with 2.5% acetonitrile-chloroform) to give the compound (12) (800 mg, 100%) as brown oil. ¹H-NMR (CDCl₃): 1.21(3H, t, J=7.4 Hz), 2.65(2H, q, J=7.4 Hz), 4.36(2H, s), 5.79 (1H, s), 6.43(1H, s), 7.20(5H, m).

(Step 2)

A mixture of the compound (12) (799 mg, 3 mmol), methyl bromoacetate (0.37 ml, 3.9 mmol), potassium carbonate (539 mg, 3.9 mmol), and 10 ml of dimethylformamide was stirred for 1 h at room temperature and to the reaction mixture was added water. The mixture was extracted with toluene, washed with water, dried over magnesium sulfate, subjected to silica gel column chromatography (20 g of silica gel, eluting with toluene) to give 797 mg of the eluate. The eluate was recrystallized from acetone and isopropyl ether to give the compound (13) (739 mg, 72.5%, melting point 120 to 121° C.) as white crystals. ¹H-NMR (CDCl₃): 1.22(3H, t, J=7.4 Hz), 2.38(3H, s), 2.65(2H, q, J=7.4 Hz), 3.83 (3H, s), 4.35(2H, s), 4.77(2H, s), 5.60(1H, s), 6.54(1H, s), 7.20(5H, s).

(Step 3)

The compound (13) (676 mg, 2 mmol) and N-methylmorpholine (0.44 ml, 4 mmol) were dissolved in 10 ml of dichloromethane. The mixture was added to a solution of oxaryl chloride (0.87 ml, 10 mmol) in 17 ml of dichloromethane, cooled to −10° C. in an ice-methanol bath, and the resulting mixture was stirred for 30 min at the same temperature. The reaction mixture was added to 10 ml of conc. aqueous ammonia and the insoluble material were filtered off. The filtrate was extracted with chloroform, washed with water, dried over magnesium sulfate, and subjected to silica gel column chromatography (30 g of silica gel, eluting with 50% of acetonitrile-chloroform). The eluate was recrystallized from acetone and ethyl acetate to give the compound (I-4) (774 mg, 94.5%, melting point 225 to 226° C.) as pale yellow crystals. ¹H-NMR (d₆-DMSO): 1.02(3H, t, J=7.2 Hz), 2.41(3H, s), 2.76(2H, q, J=7.2 Hz), 3.72(2H, s), 4.32(2H, s), 4.95(2H, s), 6.50(1H, s), 7.15-7.30(5H, m), 7.36(1H, br.s), 7.75(1H, br.s).

(Step 4)

The compound (I-5) was synthesized in a manner similar to that described in Example 1—Step 13. ¹H-NMR (d₆-DMSO): 1.02(3H, t, J=7.5 Hz), 2.40(2H, s), 2.76(2H, q, J=7.5 Hz), 4.32(2H, s), 4.84(2H, s), 6.44(1H, s), 7.16-7.28(5H, m), 7.36(1H, br.s), 7.75(1H, br.s).

Example 3

(Step 1)

A mixture of the compound (14) (25.8 g, 0.203 mol), bromoacetaldehyde diethylacetal (48.0 g, 0.244 mol), potassium carbonate (33.7 g, 0.244 mol), and 130 ml of dimethylformamide was heated for 24 h at 110° C. under nitrogen. Dimethylformamide was removed under reduced pressure and water was added to the residue. The mixture was extracted with toluene, washed with water, dried over magnesium sulfate, and toluene was removed under reduced pressure. The residue was distilled under reduced pressure to give the compound (15) (39.55 g, 80.1%, boiling point 99 to 102° C. (1 mmHg)) as colorless liquid. ¹HNMR(CDCl₃): 1.38 (3H, t, J=7.0 Hz), 1.21 (3H, t, J=7.0 Hz), 1.62 (3H, s), 2.01(1H, m, J=14.2 Hz, J=4.2 Hz), 2.40 (1H, m, J=14.2 Hz, J=7.4 Hz), 3.49-3.75 (4H, m), 4.24(1H, q, J=7.0 Hz), 4.25 (1H, q, J=7.0 Hz), 4.75(1H, m, J=7.4 Hz, J=4.2 Hz).

(Step 2)

A mixture of the compound (15) (43.6 g, 0.179 mol), potassium acetate (19.3 g, 0.197 mol), and 87 ml of dimethylsulfoxide was heated for 14 h in the oil bath (160° C.) under nitrogen. After the mixture was cooled, water was added to the mixture, and the mixture was extracted with ether. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was distilled under reduced pressure to give the compound (16) (29.48 g, 96.0%, boiling point 110-1 13° C. (23 mmHg)) as colorless liquid. ¹H-NMR (CDCl₃) : 1.22(3H, t, J=7 Hz), 1.23(3H, t, J=7 Hz), 1.35(3H, d, J=7.6 Hz), 1.73-2.00(2H, m), 2.79(1H, m), 3.47-3.80(4H, m), 4.67(1H, m).

(Step 3)

To a Grignard reagent which was prepared by magnesium (1.53 g, 0.063 mol), 71 ml of ether, 1,2-dibromoethane (0.26 ml, 0.003 mol), and benzyl bromide (7.14 ml, 0.060 mol) was added a solution of the compound (16) (7.06 g, 0.05 mol) in 35 m of ether and the resulting mixture was stirred for 4 h at room temperature and heated for 5 h under reflux in an oil bath (60° C.). To the reaction mixture were added an aqueous ammonium chloride (5.35 g, 0.1 mol, 50 ml) under ice-cooling and 63 ml of 2N sulfuric acid and the mixture was stirred for 30 min. The reaction mixture was neutralized by adding sodium bicarbonate (3.36 g, 0.040 mol) and extracted with ether. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in toluene and purified by chromatography on silica gel (90 g, eluting with 10% ethyl acetate-toluene) to give the compound (17) (9.13 g, 78%). ¹H-NMR(CDCl₃): 1.11(3H, d, J=7 Hz), 1.58-2.24(2H, m), 2.90(1H, m), 3.77(2H, s), 3.78-3.90(4H, m), 4.87(1H, t, J=4.8 Hz), 7.14-7.37(5H, m).

(Step 4)

The compound (17) (35.9 g, 0.129 mol) and N-aminophthalimide (20.9 g, 0.129 mol) were suspended in 95% of ethanol (250 ml). To the suspension was added 1N-hydrochloric acid (13 ml, 0.013 mol) and the resulting mixture was heated for 30 min under reflux in an oil bath. After cooling, the precipitated crystals were filtered to give the compound (18) (35.96 g, 84.4%, melting point 151 to 152° C.) as pale yellow crystals. ¹H-NMR (CDCl₃): 1.22(3H, t, J=7.4 Hz), 2.52(2H, q, J=7.8 Hz), 3.81(2H, s), 6.24(1H, d, J=3 Hz), 6.60(1H, d, J=3 Hz), 6.92-7.03(5H, m), 7.79(4H, m).

(Step 4′)

To a solution of the compound (17) (1.69 g, 8.6 mmol) and ethyl carbazate (0.90 g, 8.6 mmol) in 20 ml of dioxane was added 5N-hydrochloric acid (0.86 ml, 4.3 mmol) and the resulting mixture was heated for 30 min in an oil bath (100° C.). Dioxane was removed under reduced pressure and water was added to the residue. The mixture was alkalized with aq. sodium bicarbonate, extracted with toluene, dried over magnesium sulfate, subjected to silica gel column chromatography (50 g of silica gel, eluting with toluene) to give the compound (19) (0.734 g, 33.1%) as colorless oil. ¹H-NMR(CDCl₃): 1.21(3H, br.t), 2.08(3H, s), 3.84(2H, s), 4.10(2H, br), 5.98(1H, d, J=3 Hz), 6.55(1H, d, J=3 Hz), 6.79(1H, br), 7.07-7.30(5H, m).

(Step 5)

Using the compound (18) or the compound (19) as a starting material, compound (XII-2) was synthesized in a manner similar to that described in Example 1 —Step 7.

The compound (XII-3) to the compound (XII-10) were synthesized by carrying out the same reactions as described above. The physical data of each compound are shown in Tables 1.

TABLE 1

Compound No. R¹ R² ¹H-NMR(CDCl₃) XII-2

Me 2.08(3H, s), 3.98(2H, s), 5.88 (1H, s), 6.62(1H, br.s), 7.09-7.30 (5H, m) XII-3

Et 1.15(3H, t, J=7.5Hz), 2.45(2H, q, J=7.5Hz), 3.96(2H, s), 5.94 (1H, s), 6.64(1H, br.s), 6.91-7.07 (4H, m) XII-4

Et 1.13(3H, t, J=7.5Hz), 2.43(2H, q, J=7.5Hz), 4.00(2H, s), 5.94 (1H, s), 6.67(1H, br.s), 6.83-7.23 (4H, m) XII-5

Et 1.09(3H, t, J=7.2Hz), 2.34(2H; q, J=7.2Hz), 3.89(2H, s), 5.88(1H, s), 6.57(1H, br.s), 6.93(1H, m), 7.23-7.46(9H, m) XII-6

Et 1.13(3H, t, J=7.8Hz), 2.43(2H, q, J=7.8Hz), 3.97(2H, s), 5.92(1H, s), 6.63(1H, br.s), 6.81-7.37(10H, m) XII-7 Me Me 2.09(3H, s), 3.98(2H, s), 5.88(1H, s), 6.61(1H, br.s), 7.08-7.31(5H, m) XII-8

Me 1.96(3H, s), 3.86(2H, s), 5.83(1H, s), 6.91(1H, br.s), 7.07-7.34(8H, s) XII-9

Me 2.10(3H, s), 4.03(2H, s), 5.90(1H, s), 6.70(1H, br.s), 7.15-7.57(9H, m) XII-10

Et 1.08(3H, t, J=7.5Hz), 2.32(2H, q, J=7.5Hz), 3.86(2H, s), 5.90(1H, s), 6.60(1H, br.s), 7.12-7.33(8H, m)

Example 4

(Step 1)

A mixture of the compound (XII-1) (11.06 g, 54.5 mmol), ethyl 4-chloroacetoacetate (8.97 g, 54.5 mmol), p-toluenesulfonic acid monohydrate (518 mg, 2.73 mmol), and 180 ml of chloroform was heated for 4h under reflux. The generated water in situ was dehydrated by a Dean-Stark apparatus with molecular sieve 4A. To the reaction mixture were added water and sodium bicarbonate (250 mg) and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give the compound (20) (15.17 g, 92.5%) as brown oil. ¹H-NMR(CDCl₃): 1.23 (3H, t, J=7.5 Hz), 2.68(2H, q, J=7.5 Hz), 4.36 (2H, s), 4.53 (2H, s), 6.08 (1H, s), 6.51 (1H, s), 7.14-7.24 (5H, m).

(Step 2)

A mixture of the compound (20) (1.49 g, 4.95 mmol), methyl bromoacetate (0.61 ml, 6.44 mmol), potassium carbonate (684 mg, 4.95 mmol) and 15 ml of dimethylformamide was stirred for 1 h at room temperature. To the reaction mixture was added water and the mixture was extracted with toluene. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to silica gel (28 g) column chromatography, the fractions eluting with toluene were collected, and concentrated in vacuo. The residue (1.40 g) was recrystallized from ether and petroleum ether to give the compound (21) (1.19 g, 64.4%, melting point 73-73.5° C.) as white crystals. ¹H-NMR(CDCl₃): 1.23 (3H, t, J=7.5 Hz), 2.67 (2H, q, J=7.5 Hz), 3.84 (3H, s), 4.35 (2H, s), 4.55 (2H, s), 4.82 (2H, s), 5.89 (1H, s), 6.62 (1H, s), 7.12-7.24 (5H, m).

(Step 3)

A mixture of the compound (21) (373 mg, 1 mmol), phenol (113 mg, 1.2 mmol), potassium carbonate (166 mg, 1.2 mmol) and 10 ml of acetone was heated for 22h under reflux in an oil bath. Acetone was removed, the residue was treated with toluene, the insoluble material was filtered off, and the solvent was removed. The residue was subjected to silica gel (13 g) column chromatography, the fractions eluting with 5% ethyl acetate-toluene were collected, and concentrated in vacuo to give the compound (22) (350 mg, 81.4%) as colorless oil. ¹H-NMR(CDCl₃): 1.24 (3H, t, J=7.5 Hz), 2.69 (2H, q, J=7.5 Hz), 3.75 (3H, s), 4.3 (2H, s), 4.77(2H, s), 5.06 (2H, s), 5.96 (1H, s), 6.60 (1H, s), 6.93-7.25 (10H, m).

(Step 4)

The compound (22) (350 mg, 0.813 mmol) and N-methylmorpholine (0.18 ml, 1.63 mmol) were dissolved in 5 ml of dichloromethane. To the mixture was added a solution of oxalyl chloride (0.21 ml, 2.44 mmol) in 3 ml of dichloromethane which was cooled under ice-cooling and the resulting mixture was stirred for 2 h at the same temperature. The reaction mixture was poured into 2 ml of conc. aqueous ammonia under ice-cooling, the insoluble material was filtered off, and the filtrate was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to silica gel (12 g) column chromatography, the fractions eluting with 50% acetonitrile-chloroform were collected, and concentrated in vacuo. The residue was recrystallized from acetone and ethyl acetate to give the compound (I-6) (375 mg, 91.9%, melting point 185-186° C.) as pale yellow crystals. ¹H-NMR (d₆-DMSO): 1.04 (3H, t, J=7.2 Hz), 2.79 (2H, q, J=7.2 Hz), 3.67 (2H, s), 4.33 (2H, s), 4.99 (2H, s), 5.15 (2H, s), 6.68 (1H, s), 6.93-7.29 (10H, m), 7.40 (1H, br.s), 7.79 (1H, br.s).

Example 5

(Step 1)

The compound (21) (5.0 g, 13.4 mmol) and N, N-diisopropyl-N-ethylamine (3.5 ml, 20.1 mmol) were dissolved in 25 ml of dichloromethane. This solution was added to a solution of oxalyl chloride (3.5 ml, 40.2 mmol) in 35 ml of dichloromethane which was cooled in an ice-methanol bath (−10° C.) and the mixture was stirred for 2 h at the same temperature. The reaction mixture was poured into a mixed solution of conc. aqueous ammonia (10.7 ml) and chloroform (40 ml) under ice-cooling. The insoluble material was remove by filtration and the filtrate was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to silica gel (42 g) column chromatography, the fractions eluting with 50% acetonitrile and chloroform were collected, and concentrated in vacuo. The residue was recrystallized from tetrahydrofuran-ethyl acetate to give the compound (23) (5.36 g, 90.0%, melting point 191-194° C.) as pale yellow crystals. ¹H-NMR (d₆-DMSO): 1.03 (3H, t, J=7.5 Hz), 2.78 (2H, q, J=7.5 Hz), 3.72 (2H, s), 4.34 (2H, s), 4.76 (2H, s), 5.00 (2H, s), 6.71 (1H, s), 7.16-7.28 (5H, m), 7.42 (1H, br.s), 7.82 (1H, br.s).

(Step 2)

A mixture of the compound (23) (500 mg, 1.13 mmol), 4-fluorophenol (152 mg, 1.35 mmol), potassium carbonate (187 mg, 1.35 mmol), potassium iodide (38 mg, 0.226 mmol), and 20 ml of acetone was heated for 7 h under reflux in an oil bath. Acetone was removed, the residue was treated with toluene, the insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was subjected to silica gel (9.4 g) column chromatography, the fractions eluting with 5% ethyl acetate-toluene were collected, and concentrated in vacuo. The residue was recrystallized from tetrahydrofuran and ethyl acetate to give the compound (I-7) (419 mg, 71.6%, melting point 178-179° C.) as white crystals. ¹H-NMR (CDCl₃): 1.04 (3H, t, J=7.5 Hz), 2.79 (2H, q, J=7.5 Hz), 3.68 (3H, s), 4.33 (2H, s), 5.00 (2H, s), 5.13 (2H, s), 6.68 (1H, s), 7.00-7.24 (9H, m), 7.40 (1H, br.s), 7.80 (1H, br.s).

Example 6-Example 86

The compounds (I-8) to (I-84) represented by the following formula were synthesized by the same reactions described in the above Examples. The physical data were shown in Tables 2 to 11.

Provided that A in the Tables means a group represented by the following formula:

TABLE 2 Compound m.p No. R¹ R² R⁵ R^(M) (° C.) ¹H-NMR(d₆-DMSO) I-8 

Et Et Me 183-185 1.16(3H, t, J=75Hz), 1.26(3H, t, J=7.5Hz), 2.73(2H, q, J=7.5 Hz), 2.85(2H, q, J=7.5Hz), 3.80(3H, s), 4.33(2H, s), 4.74 (2H, s), 5.54(1H, br), 5.94(1H, s), 6.67(1H, br), 7.14-7.28(5H, m) I-9 

Et n-Pr Me 204-206 0.93(3H, t, J=7.2Hz), 1.16(3H, t, J=7.5Hz), 1.70(2H, m, J=7.2 Hz), 2.66(2H, t, J=7.2Hz), 2.85 (2H, q, J=7.5Hz), 3.79(3H, s), 4.33(2H, s), 4.74(2H, s), 5.56 (1H, br), 5.93(1H, s), 6.68(1H, br), 7.12-7.27(5H, m) I-10

Et i-Pr Me 174-175 1.17(3H, t, J=7.2Hz), 1.25(6H, d, J=7.2Hz), 2.87(2H, q, J=7.2 Hz), 2.96(1H, m, J=7.2Hz), 3.80(3H, s), 4.32(2H, s), 4.75 (2H, s), 5.53(1H, br.s), 5.96 (1H, s), 6.67(1H, br.s), 7.13- 7.30(5H, m) I-11

Et Ph Me 236-239 1.09(3H, t, J=7.4Hz), 2.84(2H, q, J=7.4Hz), 3.72(3H, s), 4.42 (2H, s), 5.14(2H, s), 7.10-8.05 (10H, m), 7.42(1H, br.s), 7.82 (1H, br.s) I-12

Et Me Me 252-254 1.02(3H, t, J=7.2Hz), 2.41(3H, s), 2.76(2H, q, J=7.2Hz), 3.72 (3H, s), 4.30(2H, s), 4.95(2H, s), 6.50(1H, s), 7.07(2H, t, J=8.7Hz), 7.23(2H, m), 7.35 (1H, br.s), 7.74(1H, br.s), 8.00- 8.04(2H, m) I-13

Et Ph Me 253-255 1.09(3H, t, J=7.5Hz), 2.84(2H, q, J=7.5Hz), 3.72(3H, s), 4.41 (2H, s), 5.14(2H, s), 7.09(1H, t, J=9.0Hz), 7.10(1H, s), 7.30 (2H, dd, J=9.0, 5.7Hz), 7.41 (1H, br.s), 7.50-7.58(3H, m), 7.81(1H, br.s), 8.00-8.04(2H, m)

TABLE 3 Compound m.p. No. R¹ R² R⁵ R^(M) (° C.) ¹H-NMR(d₆-DMSO) I-14

Et CF₃ Me 200-202 1.18(3H, t, J=7.5Hz), 2.88(2H, q, J=7.5Hz), 3.82(3H, s), 4.32 (2H, s), 4.81(2H, s), 5.58(1H, br.s) 6.29(1H, s), 6.77(1H, br.s), 6.93(2H, t, J=8.7Hz), 7.23(2H, dd, J=8.7, 5.4Hz) (by CDCl₃) I-15

Et Ph Me 244-246 1.09(3H, t, J=7.5Hz), 2.83(2H, q, J=7.5Hz), 3.72(3H, s), 4.43 (2H, s), 5.14(2H, s), 7.03-7.28 (5H, m), 7.42(1H, br.s), 7.49- 7.56(3H, m), 7.81(1H, br.s), 7.97-8.01(2H, m) I-16

Me Me H 271-272 (d) 2.33(3H, s), 2.41(3H, s), 4.31 (2H, s), 4.84(2H, s), 6.45(1H, s), 7.12-7.30(5H, m), 7.39(1H, br.s), 7.75(1H, br.s) I-17

Me Ph H 253-254 (d) 2.42(3H, s), 4.41(2H, s), 5.05 (2H, s), 7.05(1H, s), 7.16-8.07 (10H, m), 7.44(1H, s), 7.81(1H, s) I-18

Et Et H 223-225 (d) 1.04(3H, t, J=7.2Hz), 1.21(3H, t, J=7.2Hz), 2.70(2H, q, J=7.5 Hz), 2.79(2H, q, J=7.5Hz), 4.31(2H, s), 4.84(2H, s), 6.45 (1H, s), 7.15-7.28(5H, m), 7.36 (1H, br.s), 7.75(1H, br.s) I-19

Et n-Pr H 231-233 (d) 0.87(3H, t, J=7.2Hz), 1.04(3H, t, J=7.2Hz), 1.67(2H, m, J=7.5 Hz), 2.65(2H, q, J=7.2Hz), 2.79(2H, q, J=7.5Hz), 4.31 (2H, s), 4.86(2H, s), 6.46(1H, s), 7.13-7.25(5H, m), 7.36(1H, s), 7.75(1H, s) I-20

Et i-Pr H 234-236 (d) 1.06(3H, t, J=7.2Hz), 1.23(6H, d, J=6.6Hz), 2.81(2H, q, J=7.5 Hz), 2.98(1H, m, J=6.6Hz), 4.30(2H, s), 4.87(2H, s), 6.48 (1H, s), 7.14-7.28(5H, m), 7.36 (1H, br.s), 7.75(1H, br.s) I-21

Et Ph H 244-246 (d) 1.09(3H, t, J=7.2Hz), 2.85(2H, q, J=7.2Hz), 4.42(2H, s), 5.04 (2H, s), 7.04(1H, s), 7.14-8.03 (10H, m), 7.43(1H, br.s), 7.81 (1H, br.s)

TABLE 4 Compound m.p. No. R¹ R² R⁵ R^(M) (° C.) ¹H-NMR(d₆-DMSO) I-22

Et Me H 238-240 1.03(3H, t, J=7.5Hz), 2.40(3H, s), 2.76(2H, q, J=7.5Hz), 4.30 (2H, s), 4.84(2H, s), 6.45(1H, s), 7.07(2H, t, J=8.7Hz), 7.23 (2H, dd, J=8.7, 5.7Hz), 7.37(1H, br.s), 7.75(1H, br.s), 13.26(1H, br. s) I-23

Et Ph H 250-252 1.09(3H, t, J=7.5Hz), 2.84(2H, q, J=7.5Hz), 4.41(2H, s), 5.04 (2H, s), 7.04(1H, s), 7.09(2H, t, J=8.7Hz), 7.31(2H, dd, J=8.7, 5.7Hz), 7.43(1H, br.s), 7.50- 7.58(3H, m), 7.81(1H, br.s), 8.00-8.04(2H, m), 13.26(1H, br.s) I-24

Et CF₃ H 248-250 1.06(3H, t, J=7.5Hz), 2.83(2H, q, J=7.5Hz), 4.35(2H, s), 5.04 (2H, s), 6.97(1H, s), 7.09(2H, t, J=8.7Hz), 7.26(2H, dd, J=8.7, 5.7Hz), 7.53(1H, br.s), 7.90 (1H, br.s), 13.40(1H, br.s) I-25

Et Ph H 252-254 1.09(3H, t, J=7.5Hz), 2.83(2H, q, J=7.5Hz), 4.43(2H, s), 5.04 (2H, s), 7.03-7.28(5H, m), 7.44 (1H, br.s), 7.48-7.57(3H, m), 7.82(1H, br.s), 7.96-8.01(2H, m), 13.26(1H, br.s) I-26

Me Me Me 163-165 2.33(3H, s), 2.41(3H, s), 3.71 (3H, s), 4.31(2H, s), 3.95(2H, s), 6.49(1H, s), 7.13-7.30(5H, m), 7.37(1H, br.s), 7.77(1H, br.s) I-27

Et —CH₂SPh Me 189-192 0.99(3H, t, J=7.2Hz), 2.75(2H, q, J=7.2Hz), 3.70(3H, s), 4.25 (2H, s), 4.29(2H, s), 4.93(2H, s), 6.62(1H, s), 7.14-7.38(11H, m), 7.77(1H, br.s) I-28

Et —CH₂Cl Bn 172-173 1.14(3H, t, J=7.5Hz), 2.84(2H, q, J=7.5Hz), 2.34(2H, s), 4.50 (2H, s), 4.80(2H, s), 5.24(2H, s), 5.41(1H, br.s), 6.17(1H, s), 6.58(1H, br.s), 7.22(5H, m), 7.36(5H, s)

TABLE 5 Compound m.p. No. R¹ R² R⁵ R^(M) (° C.) ¹H-NMR(d₆-DMSO) I-29

Et

Bn 185-186 1.16(3H, t, J=7.2Hz), 1.76(4H, br,s), 2.48(4H, br.s), 2.85(2H, q, J=7.2Hz), 3.63(2H, s), 4.34 (2H, s), 4.81(2H, s), 5.22(2H, s), 5.36(1H, br.s), 6.33(1H, s), 6.54(1H, br.s), 7.22(5H, m),7.36(5H, s) I-30

Et

Bn 183-184 1.17(3H, t, J=7.4Hz), 2.37(4H, m), 2.86.(2H, q, J=7.4Hz), 3.47 (2H, s), 3.63(4H, m), 4.32(2H, s), 4.80(2H, s), 5.22(2H, s), 5.40(1H, br.s), 6.27(1H, s), 6.56(1H, br.s), 7.12-7.22(5H, m), 7.35(5H, s) I-31

Et

Bn 202-203 1.17(3H, t, J=7.2Hz), 2.29(3H, s), 2.43(8H, br.s), 2.86(2H, q, J=7.2Hz), 3.48(2H, s), 4.32 (2H, s), 4.79(2H, s), 5.22(2H, s), 5.39(1H, br.s), 6.28(1H, s), 6.55(1H, br.s), 7.16-7.24(5H, m), 7.35(5H, s) I-32

Et

Me 274-276 (d) 1.09(3H, t, J=7.2Hz), 2.84(2H, q, J=7.2Hz), 2.72(3H, s), 4.40 (2H, s), 5.13(2H, s), 7.06-7.42 (8H, m), 7.81(1H, br.s), 8.07- 8.12(2H, m) I-33

Et

Me 249-253 (d) 1.08(3H, t, J=7.2Hz), 2.84(2H, q, J=7.2Hz), 3.72(3H, s), 4.42 (2H, s), 5.13(2H, s), 7.10-7.41 (9H, m), 7.80(1H, br.s), 8.06- 8.11(2H, m) I-34

Et

Me 215-217 (d) 1.09(3H, t, J=7.5Hz), 2.84(2H, q, J=7.5Hz), 2.72(3H, s), 3.83 (3H, s), 4.40(2H, s), 5.13(2H, s), 7.04-7.28(8H, m), 7.40(1H, br.s), 7.79(1H, br.s), 7.99(2H, d, J=8.7Hz) I-35

Et Me Me 187-189 0.89(3H, t, J=7.2Hz), 2.34(3H, s), 2.55(2H, q, J=7.2Hz), 3.72 (3H, s), 4.25(2H, s), 4.93(2H, s), 6.45(1H, s), 6.85-7.48(10H, m), 7.72(1H, br.s) I-36

Et Me Me 201-202 1.01(3H, t, J=7.4Hz), 2.34(3H, s), 2.76(2H, J=7.4Hz), 3.72 (3H, s), 4.28(2H, s), 4.94(2H, s), 6.48(1H, s), 6.79-7.41(10H, m), 7.74(1H, br.s)

TABLE 6 Compound m.p. No. R¹ R² R⁵ R^(M) (° C.) ¹H-NMR(d₆-DMSO) I-37

Et

Me 207-209 (d) 1.04(3H, t, J=7.5Hz), 1.20-1.90 (10H, m), 2.59-2.70(1H, m), 2.79(2H, q, J=7.5Hz), 3.71 (3H, s), 4.30(2H, s), 4.97(2H, s), 6.54(1H, s), 7.12-7.26(5H, m), 7.34(1H, br.s), 7.74(1H, br.s) I-38

Et

Me 160-162 (d) 1.06(3H, t, J=7.5Hz), 1.56-2.01 (8H, m), 2.80(2H, q, J=7.5Hz), 3.08-3.18(1H, m), 3.71(3H, s), 4.29(2H, s), 4.98(2H, s), 6.49 (1H, s), 7.13-7.27(5H, m), 7.35 (1H, br.s), 7.74(1H, br.s) I-39

Et

Me 245-247 (d) 1.09(3H, t, J=7.5Hz), 2.84 (2H, q, J=7.5Hz), 3.72(3H, s), 4.40(2H, s), 5.12(2H, s), 6.11 (2H, s), 7.04(1H, s), 7.07(1H, d), 7.13-7.28(5H, m), 7.41(1H, br.s), 7.56-7.61(2H, m), 7.80 (1H, br.s) I-40

Me Et Me 194-196 1.23(3H, t, J=7.4Hz), 2.35(3H, s), 2.72(2H, q, J=7.4Hz), 3.71 (3H, s), 4.30(2H, s), 4.96(2H, s), 6.51(1H, s), 7.20-7.25(5H, m), 7.36(1H, br.s), 7.74(1H, br.s) I-41

Me n-Pr Me 210-211 0.89(3H, t, J=7.4Hz), 1.69(2H, m, J=7.4Hz), 2.35(3H, s), 2.67 (2H, t, J=7.4Hz), 3.71(3H, s), 4.30(2H, s), 4.96(2H, s), 6.51 (1H, s), 7.12-7.23(5H, m), 7.36 (1H, br.s), 7.75(1H, br.s) I-42

Me

Me 204-206 2.37(3H, s), 3.65(3H, s), 4.02 (2H, s), 4.28(2H, s), 4.92(2H, s), 6.52(1H, s), 7.21(5H, m), 7.26(5H, m), 7.35(1H, br.s), 7.74(1H, br.s) I-43

Me MeSCH₂— Me 210-211 1.80(3H, s), 2.36(3H, s), 3.70 (5H, s), 4.30(2H, s), 4.96(2H, s), 6.58(1H, s), 7.10-7.26(5H, m), 7.39(1H, br.s), 7.77(1H, br.s) I-44

Me MeOCH₂— Me 228-229 (d) 2.35(3H, s), 3.29(3H, s), 3.71 (3H, s), 4.32(2H, s), 4.46(2H, s), 5.00(2H, s), 6.55(1H, s), 7.13-7.30(5H, m), 7.39(1H, br.s), 7.77(1H, br.s)

TABLE 7 Compound m.p. No. R¹ R² R⁵ R^(M) (° C.) ¹H-NMR(d₆-DMSO) I-45

Me Ph Me 251-252 2.42(3H, s), 3.71(3H, s), 4.41 (2H, s), 5.14(2H, s), 3.10(1H, s), 7.16-8.06(10H, m), 7.46(1H, br.s), 7.81(1H, br.s) I-46

Et

Me 167-168 1.04(3H, t, J=7.5Hz), 2.79(2H, q, J=7.5Hz), 3.68(3H, s), 4.33 (2H, s), 4.99(2H, s), 5.08(2H, s), 6.66(1H, s), 6.80(2H, d, J=9 Hz), 6.92(2H, d, J=9Hz), 7.17- 7.28(5H, m), 7.40(1H, s), 7.79 (1H, br.s) I-47

Et

Me 176-179 1.03(3H, t, J=7.4Hz), 2.79(2H, q, J=7.4Hz), 3.67(3H, s), 3.68 (3H, s), 3.71(3H, s), 4.34(2H, s), 5.00(2H, s), 5.09(2H, s), 6.45-7.28(8H, m), 7.41(1H, br.s), 7.80(1H, br.s) I-48

Et

Me 191-192 1.04(3H, t, J=7.2Hz), 2.21(3H, s), 2.79(2H, q, J=7.2Hz), 3.67 (3H, s), 4.33(2H, s), 4.99(2H, s), 5.11(2H, s), 6.66(1H, s), 6.88(2H, d, J=9Hz), 7.05(2H, d, J=9Hz), 7.16-7.28(5H, m), 7.39(1H, br.s), 7.79(1H, br.s) I-49

Et

Me 188-189 1.04(3H, t, J=7.0Hz), 2.60(4H, s), 2.78(2H, J=7.0Hz), 3.73 (3H, s), 4.22(2H, s), 4.66(2H, s), 4.97(2H, s), 6.54(1H, s), 7.20-7.28(5H, m), 7.40(1H, br.s), 7.79(1H, br.s) I-50

Et N₃CH₂— Bn 178-179 1.03(3H, t, J=7.4Hz), 2.79(2H, q, J=7.4Hz), 4.35(2H, s), 4.49 (2H, s), 5.07(2H, s), 5.21(2H, s), 6.63(1H, s), 7.12-7.36(10H, m), 7.41(1H, br.s), 7.81(1H, br.s) I-51 Me Me

Me 199-201 2.29(3H, s), 2.43(3H, s), 3.63 (3H, s), 4.04(2H, s), 4.92(2H, s), 6.46(1H, s), 7.21-7.32(6H, m), 7.71(1H, br.s) I-52

Me Me Me 194-196 2.18(3H, s), 2.37(3H, s), 3.79 (3H, s), 4.24(2H, s), 4.74(2H, s), 5.91(1H, s), 5.94(1H, br.s), 6.71(1H, br.s), 6.98-7.38(8H, m)

TABLE 8 Compound m.p. No. R¹ R² R⁵ R^(M) (° C.) ¹H-NMR(d₆-DMSO) I-53

Me Me Me 234-236 2.44(3H, s), 2.46(3H, s), 3.80 (3H, s), 4.37(2H, s), 4.75(2H, s), 5.45(1H, br.s), 5.96(1H, s), 6.67(1H, br.s), 7.29-7.56(9H, m) I-54

Et Me Me 190-192 0.96(3H, t, J=7.2Hz), 2.37(3H, s), 2.60(2H, q, J=7.2 Hz), 3.81 (3H, s), 4.25(2H, s), 4.73(2H, s), 5.43(1H, br.s), 5.90(1H, s), 6.60(1H, br.s), 6.95-7.37(8H, m) I-55

Me Me Et 197-199 1.21(3H, t, J=7.2Hz), 2.32(3H, s), 2.41(3H, s), 4.18(2H, q, J=7.2Hz), 4.31(2H, s), 4.93 (2H, s), 6.47(1H, s), 7.16-7.28 (5H, m), 7.35(1H, br.s), 7.72 (1H, br.s) I-56

Me Me A 160-161 2.41(3H, s), 2.44(3H, s), 2.50 (4H, br.s), 2.65(2H, br.s), 3.71 (4H, m), 4.33(4H, s), 4.75(2H, s), 5.94(1H, br), 5.98(1H, s), 6.94(1H, br), 7.15-7.24(5H, m) I-57

Et

H 218-220 (d) 1.04(3H, t, J=7.5Hz), 2.80(2H, q, J=7.5Hz), 4.34(2H, s), 4.88 (2H, s), 5.14(2H, s), 6.66(1H, s), 6.93-7.30(10H, m), 7.41(1H, br.s), 7.80(1H, br.s) I-58

Et

H 226-228 (d) 0.99(3H, t, J=7.2Hz), 2.74(2H, q, J=7.2Hz), 4.25(2H, s), 4.28 (2H, s), 4.83(2H, s), 6.60(1H, s), 7.14-7.39(11H, m), 7.78(1H, br.s), 13.33(1H, br) I-59

Et

H 228-231 (d) 1.05(3H, t, J=7.4Hz), 1.77(4H, br.s), 2.80(2H, q, J=7.4Hz), 2.86(4H, br.s), 4.09(2H, s), 4.34(2H, s), 4.66(2H, s), 6.65 (1H, s), 7.16-7.28(5H, m) I-60

Et

H 167-168 1.06(3H, t, J=7.2Hz), 2.35(4H, m), 2.80(2H, q, J=7.2Hz), 3.53 (4H, m), 4.31(2H, s), 4.87(2H, s), 6.50(1H, s), 7.12-7.24(5H, m), 7.39(1H, br.s), 7.78(1H, br.s)

TABLE 9 Compound m.p. No. R¹ R² R⁵ R^(M) (° C.) ¹H-NMR(d₆-DMSO) I-61

Et

H 249-250 (d) 1.05(3H, t, J=7.2Hz), 2.32(3H, s), 2.44(4H, br.s), 2.55(4H, br.s), 2.79(2H, q, J=7.2Hz), 3.52(2H, s), 4.31(2H, s), 4.67 (2H, s), 6.39(1H, s), 7.10-7.25 (5H, m), 7.37(1H, br.s), 7.79 (1H, br.s) I-62

Et

H 245-248 (d) 1.09(3H t, J=7.5Hz), 2.84(2H, q, J=7.5Hz), 4.40(2H, s), 5.04 (2H, s), 7.05-7.43(8H, m), 7.82 (1H, br.s), 8.06-8.12(2H, m) I-63

Et

H 250-253 (d) 1.09(3H, t, J=7.5Hz), 2.84(2H, q, J=7.5Hz), 4.41(2H, s), 5.04 (2H, s), 7.05(1H, s), 7.13-7.43 (8H, m), 7.82(1H, br.s), 8.05- 8.11(2H, m) I-64

Et

H 248-250 (d) 1.09(3H, t, J=7.5Hz), 2.84(2H, q, J=7.5Hz), 3.82(3H, s), 4.40 (2H, s), 4.99(2H, s), 6.96(1H, s), 7.06(2H, d, J=8.7Hz), 7.14-7.27(5H, m), 7.41(1H, br.s), 7.80(1H, br.s), 7.96(2H, d, J=8.7Hz) I-65

Et Me H 218-219 (d) 0.90(3H, t, J=7.2Hz), 2.33(3H, s), 2.55(2H, q, J=7.2Hz), 4.24 (2H, s), 4.83(2H, s), 6.39(1H, s), 6.85-7.47(9H, m), 7.73(1H, br.s) I-66

Et Me H 188-190 1.02(3H, t, J=7.0Hz), 2.34(3H, s), 2.76(2H, q, J=7.0Hz), 4.28 (2H, s), 4.84(2H, s), 6.44(1H, s), 6.80-7.41(10H, m), 7.75(1H, br.s) I-67

Et

H 272-275 (d) 1.04(3H, t, J=7.5Hz), 1.20-1.90 (10H, m), 2.50-2.70(1H, 2.79(2H, q, J=7.5Hz), 4.30 (2H, s), 4.86(2H, s), 6.48(1H, s), 7.12-7.26(5H, m), 7.36(1H, br.s), 7.75(1H, br.s), 13.24(1H, br.s) I-68

Et

H 250-252 (d) 1.06(3H, t, J=7.2Hz), 1.55-2.01 (8H, m), 2.80(2H, q, J=7.2Hz), 3.06-3.18(1H, m), 4.29(2H, s), 4.87(2H, s), 6.44(1H, s), 7.12- 7.27(5H, m), 7.37(1H, br.s), 7.75(1H, br.s), 13.30(1H, br.s)

TABLE 10 Compound m.p. No. R¹ R² R⁵ R^(M) (° C.) ¹H-NMR(d₆-DMSO) I-69

Et

H 240-243 (d) 1.09(3H, t, J=7.5Hz), 2.84(2H, q, J=7.5Hz), 4.40(2H, s), 5.01 (2H, s), 6.11(2H, s), 6.98(1H, s), 7.06(1H, d, J=8.1Hz), 7.13- 7.30(5H, m), 7.42(1H, br.s), 7.55-7.59(2H, m), 7.81(1H, br.s), 13.25(1H, br.s) I-70

Me Et H 200-201 1.22(3H, t, J=7.6Hz), 2.35(2H, s), 2.71(2H, q, J=7.6Hz), 4.30 (2H, s), 4.86(2H, s), 6.46(1H, s), 7.23(5H, m), 7.38(1H, br.s), 7.74(1H, br.s) I-71

Me n-Pr H 204-205 0.88(3H, t, J=7.0Hz), 1.68(2H, m), 2.35(3H, s), 2.66(2H, t, J=7.0Hz), 4.30(2H, s), 4.85 (2H, s), 6.46(1H, s), 7.22(5H, m), 7.34(1H, br.s), 7.74(1H, br.s) I-72

Me

H 245-247 (d) 2.37(3H, s), 4.01(2H, s), 4.28 (2H, s), 4.82(2H, s), 6.52(1H, s), 7.20(5H, m), 7.25(5H, m), 7.37(1H, br.s), 7.74(1H, br.s) I-73

Me MeSCH₂— H 228-229 (d) 1.89(3H, s), 2.36(3H, s), 3.71 (2H, s), 4.30(2H, s), 4.85(2H, s), 6.54(1H, s), 7.22(5H, m), 7.40(1H, br.s), 7.78(1H, br.s) I-74

Me MeOCH₂— H 197-198 2.35(3H, s), 3.29(3H, s), 4.32 (2H, s), 4.44(2H, s), 4.89(2H, s), 6.49(1H, s), 7.22(5H, m), 7.41(1H, br.s), 7.78(1H, br.s), 13.28(1H, br) I-75

Et

H 215-216 1.04(3H, t, J=7.2Hz), 2.79(2H, q, J=7.2Hz), 4.32(2H, s), 4.89 (2H, s), 5.13(2H, s), 6.65(1H, s), 6.97-7.25(9H, m), 7.41(1H, br.s), 7.79(1H, br.s), 13.30(1H, br.s) I-76

Et

H 218-219 1.04(3H, t, 7.4Hz), 2.79(2H, q, J=7.4Hz), 3.68(3H, s), 4.33 (2H, s), 4.88(2H, s), 5.07(2H, s), 6.63(1H, s), 6.79(2H, d, J=9.2Hz), 6.93(2H, d, J=9.2 Hz), 7.15-7.23(5H, m), 7.40 (1H, br.s), 7.79(1H, br.s), 13.2 (1H, br)

TABLE 11 Compound m.p. No. R¹ R² R⁵ R^(M) (° C.) ¹H-NMR(d₆-DMSO) I-77

Et

H 204-206 1.03(3H, t, J=7.4Hz), 2.78(2H, q, J=7.4Hz), 3.67(3H, s), 3.71 (3H, s), 4.33(2H, s), 4.88(2H, s), 5.07(2H, s), 6.49(1H, d of d, J=8.8Hz, J=2.8Hz), 6.64(1H, s), 6.67(1H, d, J=2.8Hz), 6.77 (1H, d, J=8.8Hz), 7.20(5H, m), 7.40(1H, br.s), 7.80(1H, br.s) I-78

Et

H 219-221 1.04(3H, t, J=7.0Hz), 2.21(3H, s), 2.79(2H, q, J=7.0Hz), 4.33 (2H, s), 4.87(2H, s), 5.10(2H, s), 6.63(1H, s), 6.88(2H, d, J=8.8Hz), 7.04(2H, d, J=8.8 Hz), 7.21(5H, m), 7.41(1H, br.s), 7.79(1H, br.s), 13.3(1H, br) I-79

Et

H 210-212 (d) 1.03(3H, m), 2.39-2.46(4H, m), 2.77(2H, q, J=7.0Hz), 4.30 (2H, s) 4.33(2H, s), 4.81(2H, s), 6.38(1H, s), 7.23(5H, m), 7.38(1H, br.s), 7.76(1H, br.s) I-80

Et N₃CH₂— H 199-200 (d) 1.03(3H, t, J=7.4Hz), 2.79(2H, q, J=7.4Hz), 4.35(2H, s), 4.51 (2H, s), 4.87(2H, s), 6.59(1H, s), 7.23(5H, m), 7.42(1H, br.s), 7.80(1H, br.s), 13.3(1H, br) I-81 Me Me

H 232-233 (d) 2.30(3H, s), 2.42(3H, s), 4.04 (2H, s), 4.81(2H, s), 6.47(1H, s), 7.20-7.32(6H, m), 7.71(1H, br.s), 13.27(1H, br.s), I-82

Me Me H 242-244 (d) 2.15(3H, s), 2.30(3H, s), 4.22 (2H, s), 4.65(2H, s), 6.29(1H, s), 6.86-6.89(1H, m), 7.18-7.52 (8H, m), 7.81(1H, br.s), I-83

Me Me H 271-276 (d) 2.36(3H, s), 2.41(3H, s), 4.35 (2H, s), 4.79(2H, s), 6.42(1H, s), 7.27-7.61(10H, m), 7.77(1H, br.s) I-84

Et Me H 214-216 (d) 0.88(3H, t, J=7.2Hz), 2.31(3H, s), 2.54(2H, q, J=7.2Hz), 4.23 (2H, s); 4.75(2H, s), 6.35(1H, s), 6.87-7.42(9H, m), 7.76(1H, br.s)

The compounds shown in the following Tables 12 to 17 can be synthesized in accordance with the same method describe in the above Examples. The abbreviations used in Tables 12 to 17: AA, AB, AC, AD, AE, AF, AG, AH, AI, AJ, AK, AL, AM, AN, AO, AP, AQ AR, AS, AT, AU, AV, AW, AX, AY, BA, BB, BC, BD, BE, BF, BG, BH and BI show the substituents described as follows.

AA

AB

AC

AD

AE

AF

AG

AH

AI

AJ

AK

AL

AM

AN

AO

AP

AQ

AR

AS

AT

AU

AV

AW

AX

AY

AZ

BA

BB

BC

BD

BE

BF

BG

BH

BI

TABLE 12

Compound No. R³⁷ R³⁸ R³⁹ II-1  Me AA Me II-2  Me AB Me II-3  Me AC Me II-4  Me AD Me II-5  Me AE Me II-6  Me AF Me II-7  Me AG Me II-8  Me AH Me II-9  Me AI Me II-10 Me AJ Me II-11 Me AK Me II-12 Me AL Me II-13 Me AM Me II-14 Me AN Me II-15 Me AO Me II-16 Me AP Me II-17 Me AQ Me II-18 Me AR Me II-19 Me AS Me II-20 Me AT Me II-21 Me AU Me II-22 Me AV Me II-23 Me AW Me II-24 Me AX Me II-25 Me AY Me II-26 Me AZ Me II-27 Me BA Me II-28 Me BB Me II-29 Me BC Me II-30 Me BD Me II-31 Me BE Me II-32 Me BF Me II-33 Me BG Me II-34 Me BH Me II-35 Me BI Me II-36 Et AA Me II-37 Et AB Me II-38 Et AC Me II-39 Et AD Me II-40 Et AE Me II-41 Et AF Me II-42 Et AG Me II-43 Et AH Me II-44 Et AI Me II-45 Et AJ Me II-46 Et AK Me II-47 Et AL Me II-48 Et AM Me II-49 Et AN Me II-50 Et AO Me II-51 Et AP Me II-52 Et AQ Me II-53 Et AR Me II-54 Et AS Me II-55 Et AT Me II-56 Et AU Me II-57 Et AV Me II-58 Et AW Me II-59 Et AX Me II-60 Et AY Me II-61 Et AZ Me II-62 Et BA Me II-63 Et BB Me II-64 Et BC Me II-65 Et BD Me II-66 Et BE Me II-67 Et BF Me II-68 Et BG Me II-69 Et BH Me II-70 Et BI Me II-71 Ph AA Me II-72 Ph AB Me II-73 Ph AC Me II-74 Ph AD Me II-75 Ph AE Me II-76 Ph AF Me II-77 Ph AG Me II-78 Ph AH Me II-79 Ph AI Me II-80 Ph AJ Me II-81 Ph AK Me II-82 Ph AL Me II-83 Ph AM Me II-84 Ph AN Me II-85 Ph AO Me II-86 Ph AP Me II-87 Ph AQ Me II-88 Ph AR Me II-89 Ph AS Me II-90 Ph AT Me II-91 Ph AU Me II-92 Ph AV Me II-93 Ph AW Me II-94 Ph AX Me II-95 Ph AY Me II-96 Ph AZ Me II-97 Ph BA Me II-98 Ph BB Me II-99 Ph BC Me  II-100 Ph BD Me  II-101 Ph BE Me  II-102 Ph BF Me  II-103 Ph BG Me  II-104 Ph BH Me  II-105 Ph BI Me

TABLE 13

Compound No. R³⁷ R³⁸ R³⁹ II-106 Me AA Et II-107 Me AB Et II-108 Me AC Et II-109 Me AD Et II-110 Me AE Et II-111 Me AF Et II-112 Me AG Et II-113 Me AH Et II-114 Me AI Et II-115 Me AJ Et II-116 Me AK Et II-117 Me AL Et II-118 Me AM Et II-119 Me AN Et II-120 Me AO Et II-121 Me AP Et II-122 Me AQ Et II-123 Me AR Et II-124 Me AS Et II-125 Me AT Et II-126 Me AU Et II-127 Me AV Et II-128 Me AW Et II-129 Me AX Et II-130 Me AY Et II-131 Me AZ Et II-132 Me BA Et II-133 Me BB Et II-134 Me BC Et II-135 Me BD Et II-136 Me BE Et II-137 Me BF Et II-138 Me BG Et II-139 Me BH Et II-140 Me BI Et II-141 Et BA Et II-142 Et BB Et II-143 Et BC Et II-144 Et BD Et II-145 Et BE Et II-146 Et BF Et II-147 Et BG Et II-148 Et BH Et II-149 Et BI Et II-150 Et BJ Et II-151 Et BK Et II-152 Et BL Et II-153 Et BM Et II-154 Et BN Et II-155 Et BO Et II-156 Et BP Et II-157 Et BQ Et II-158 Et BR Et II-159 Et BS Et II-160 Et BT Et II-161 Et BU Et II-162 Et BV Et II-163 Et BW Et II-164 Et BX Et II-165 Et BY Et II-166 Et BZ Et II-167 Et CA Et II-168 Et CB Et II-169 Et CC Et II-170 Et CD Et II-171 Et CE Et II-172 Et CF Et II-173 Et CG Et II-174 Et CH Et II-175 Et CI Et II-176 Ph BA Et II-177 Ph BB Et II-178 Ph BC Et II-179 Ph BD Et II-180 Ph BE Et II-181 Ph BF Et II-182 Ph BG Et II-183 Ph BH Et II-184 Ph BI Et II-185 Ph BJ Et II-186 Ph BK Et II-187 Ph BL Et II-188 Ph BM Et II-189 Ph BN Et II-190 Ph BO Et II-191 Ph BP Et II-192 Ph BQ Et II-193 Ph BR Et II-194 Ph BS Et II-195 Ph BT Et II-196 Ph BU Et II-197 Ph BV Et II-198 Ph BW Et II-199 Ph BX Et II-200 Ph BY Et II-201 Ph BZ Et II-202 Ph CA Et II-203 Ph CB Et II-204 Ph CC Et II-205 Ph CD Et II-206 Ph CE Et II-207 Ph CF Et II-208 Ph CG Et II-209 Ph CH Et II-210 Ph CI Et

TABLE 14

Compound No. R³⁷ R³⁸ R³⁹ II-211 Me AA Me II-212 Me AB Me II-213 Me AC Me II-214 Me AD Me II-215 Me AE Me II-216 Me AF Me II-217 Me AG Me II-218 Me AH Me II-219 Me AI Me II-220 Me AJ Me II-221 Me AK Me II-222 Me AL Me II-223 Me AM Me II-224 Me AN Me II-225 Me AO Me II-226 Me AP Me II-227 Me AQ Me II-228 Me AR Me II-229 Me AS Me II-230 Me AT Me II-231 Me AU Me II-232 Me AV Me II-233 Me AW Me II-234 Me AX Me II-235 Me AY Me II-236 Me AZ Me II-237 Me BA Me II-238 Me BB Me II-239 Me BC Me II-240 Me BD Me II-241 Me BE Me II-242 Me BF Me II-243 Me BG Me II-244 Me BH Me II-245 Me BI Me II-246 Et AA Me II-247 Et AB Me II-248 Et AC Me II-249 Et AD Me II-250 Et AE Me II-251 Et AF Me II-252 Et AG Me II-253 Et AH Me II-254 Et AI Me II-255 Et AJ Me II-256 Et AK Me II-257 Et AL Me II-258 Et AM Me II-259 Et AN Me II-260 Et AO Me II-261 Et AP Me II-262 Et AQ Me II-263 Et AR Me II-264 Et AS Me II-265 Et AT Me II-266 Et AU Me II-267 Et AV Me II-268 Et AW Me II-269 Et AX Me II-270 Et AY Me II-271 Et AZ Me II-272 Et BA Me II-273 Et BB Me II-274 Et BC Me II-275 Et BD Me II-276 Et BE Me II-277 Et BF Me II-278 Et BG Me II-279 Et BH Me II-280 Et BI Me II-281 Ph AA Me II-282 Ph AB Me II-283 Ph AC Me II-284 Ph AD Me II-285 Ph AE Me II-286 Ph AF Me II-287 Ph AG Me II-288 Ph AH Me II-289 Ph AI Me II-290 Ph AJ Me II-291 Ph AK Me II-292 Ph AL Me II-293 Ph AM Me II-294 Ph AN Me II-295 Ph AO Me II-296 Ph AP Me II-297 Ph AQ Me II-298 Ph AR Me II-299 Ph AS Me II-300 Ph AT Me II-301 Ph AU Me II-302 Ph AV Me II-303 Ph AW Me II-304 Ph AX Me II-305 Ph AY Me II-306 Ph AZ Me II-307 Ph BA Me II-308 Ph BB Me II-309 Ph BC Me II-310 Ph BD Me II-311 Ph BE Me II-312 Ph BF Me II-313 Ph BG Me II-314 Ph BH Me II-315 Ph BI Me

TABLE 15

Compound No. R³⁷ R³⁸ R³⁹ II-316 Me AA Et II-317 Me AB Et II-318 Me AC Et II-319 Me AD Et II-320 Me AE Et II-321 Me AF Et II-322 Me AG Et II-323 Me AH Et II-324 Me AI Et II-325 Me AJ Et II-326 Me AK Et II-327 Me AL Et II-328 Me AM Et II-329 Me AN Et II-330 Me AO Et II-331 Me AP Et II-332 Me AQ Et II-333 Me AR Et II-334 Me AS Et II-335 Me AT Et II-336 Me AU Et II-337 Me AV Et II-338 Me AW Et II-339 Me AX Et II-340 Me AY Et II-341 Me AZ Et II-342 Me BA Et II-343 Me BB Et II-344 Me BC Et II-345 Me BD Et II-346 Me BE Et II-347 Me BF Et II-348 Me BG Et II-349 Me BH Et II-350 Me BI Et II-351 Et AA Et II-352 Et AB Et II-353 Et AC Et II-354 Et AD Et II-355 Et AE Et II-356 Et AF Et II-357 Et AG Et II-358 Et AH Et II-359 Et AI Et II-360 Et AJ Et II-361 Et AK Et II-362 Et AL Et II-363 Et AM Et II-364 Et AN Et II-365 Et AO Et II-366 Et AP Et II-367 Et AQ Et II-368 Et AR Et II-369 Et AS Et II-370 Et AT Et II-371 Et AU Et II-372 Et AV Et II-373 Et AW Et II-374 Et AX Et II-375 Et AY Et II-376 Et AZ Et II-377 Et BA Et II-378 Et BB Et II-379 Et BC Et II-380 Et BD Et II-381 Et BE Et II-382 Et BF Et II-383 Et BG Et II-384 Et BH Et II-385 Et BI Et II-386 Ph AA Et II-387 Ph AB Et II-388 Ph AC Et II-389 Ph AD Et II-390 Ph AE Et II-391 Ph AF Et II-392 Ph AG Et II-393 Ph AH Et II-394 Ph AI Et II-395 Ph AJ Et II-396 Ph AK Et II-397 Ph AL Et II-398 Ph AM Et II-399 Ph AN Et II-400 Ph AO Et II-401 Ph AP Et II-402 Ph AQ Et II-403 Ph AR Et II-404 Ph AS Et II-405 Ph AT Et II-406 Ph AU Et II-407 Ph AV Et II-408 Ph AW Et II-409 Ph AX Et II-410 Ph AY Et II-411 Ph AZ Et II-412 Ph BA Et II-413 Ph BB Et II-414 Ph BC Et II-415 Ph BD Et II-416 Ph BE Et II-417 Ph BF Et II-418 Ph BG Et II-419 Ph BH Et II-420 Ph BI Et

TABLE 16

Compound No. R³⁷ R³⁸ R³⁹ II-421 Me AA Me II-422 Me AB Me II-423 Me AC Me II-424 Me AD Me II-425 Me AE Me II-426 Me AF Me II-427 Me AG Me II-428 Me AH Me II-429 Me AI Me II-430 Me AJ Me II-431 Me AK Me II-432 Me AL Me II-433 Me AM Me II-434 Me AN Me II-435 Me AO Me II-436 Me AP Me II-437 Me AQ Me II-438 Me AR Me II-439 Me AS Me II-440 Me AT Me II-441 Me AU Me II-442 Me AV Me II-443 Me AW Me II-444 Me AX Me II-445 Me AY Me II-446 Me AZ Me II-447 Me BA Me II-448 Me BB Me II-449 Me BC Me II-450 Me BD Me II-451 Me BE Me II-452 Me BF Me II-453 Me BG Me II-454 Me BH Me II-455 Me BI Me II-456 Et AA Me II-457 Et AB Me II-458 Et AC Me II-459 Et AD Me II-460 Et AE Me II-461 Et AF Me II-462 Et AG Me II-463 Et AH Me II-464 Et AI Me II-465 Et AJ Me II-466 Et AK Me II-467 Et AL Me II-468 Et AM Me II-469 Et AN Me II-470 Et AO Me II-471 Et AP Me II-472 Et AQ Me II-473 Et AR Me II-474 Et AS Me II-475 Et AT Me II-476 Et AU Me II-477 Et AV Me II-478 Et AW Me II-479 Et AX Me II-480 Et AY Me II-481 Et AZ Me II-482 Et BA Me II-483 Et BB Me II-484 Et BC Me II-485 Et BD Me II-486 Et BE Me II-487 Et BF Me II-488 Et BG Me II-489 Et BH Me II-490 Et BI Me II-491 Ph AA Me II-492 Ph AB Me II-493 Ph AC Me II-494 Ph AD Me II-495 Ph AE Me II-496 Ph AF Me II-497 Ph AG Me II-498 Ph AH Me II-499 Ph AI Me II-500 Ph AJ Me II-501 Ph AK Me II-502 Ph AL Me II-503 Ph AM Me II-504 Ph AN Me II-505 Ph AO Me II-506 Ph AP Me II-507 Ph AQ Me II-508 Ph AR Me II-509 Ph AS Me II-510 Ph AT Me II-511 Ph AU Me II-512 Ph AV Me II-513 Ph AW Me II-514 Ph AX Me II-515 Ph AY Me II-516 Ph AZ Me II-517 Ph BA Me II-518 Ph BB Me II-519 Ph BC Me II-520 Ph BD Me II-521 Ph BE Me II-522 Ph BF Me II-523 Ph BG Me II-524 Ph BH Me II-525 Ph BI Me

TABLE 17

Compound No. R³⁷ R³⁸ R³⁹ II-526 Me AA Et II-527 Me AB Et II-528 Me AC Et II-529 Me AD Et II-530 Me AE Et II-531 Me AF Et II-532 Me AG Et II-533 Me AH Et II-534 Me AI Et II-535 Me AJ Et II-536 Me AK Et II-537 Me AL Et II-538 Me AM Et II-539 Me AN Et II-540 Me AO Et II-541 Me AP Et II-542 Me AQ Et II-543 Me AR Et II-544 Me AS Et II-545 Me AT Et II-546 Me AU Et II-547 Me AV Et II-548 Me AW Et II-549 Me AX Et II-550 Me AY Et II-551 Me AZ Et II-552 Me BA Et II-553 Me BB Et II-554 Me BC Et II-555 Me BD Et II-556 Me BE Et II-557 Me BF Et II-558 Me BG Et II-559 Me BH Et II-560 Me BI Et II-561 Et AA Et II-562 Et AB Et II-563 Et AC Et II-564 Et AD Et II-565 Et AE Et II-566 Et AF Et II-567 Et AG Et II-568 Et AH Et II-569 Et AI Et II-570 Et AJ Et II-571 Et AK Et II-572 Et AL Et II-573 Et AM Et II-574 Et AN Et II-575 Et AO Et II-576 Et AP Et II-577 Et AQ Et II-578 Et AR Et II-579 Et AS Et II-580 Et AT Et II-581 Et AU Et II-582 Et AV Et II-583 Et AW Et II-584 Et AX Et II-585 Et AY Et II-586 Et AZ Et II-587 Et BA Et II-588 Et BB Et II-589 Et BC Et II-590 Et BD Et II-591 Et BE Et II-592 Et BF Et II-593 Et BG Et II-594 Et BH Et II-595 Et BI Et II-596 Ph AA Et II-597 Ph AB Et II-598 Ph AC Et II-599 Ph AD Et II-600 Ph AE Et II-601 Ph AF Et II-602 Ph AG Et II-603 Ph AH Et II-604 Ph AI Et II-605 Ph AJ Et II-606 Ph AK Et II-607 Ph AL Et II-608 Ph AM Et II-609 Ph AN Et II-610 Ph AO Et II-611 Ph AP Et II-612 Ph AQ Et II-613 Ph AR Et II-614 Ph AS Et II-615 Ph AT Et II-616 Ph AU Et II-617 Ph AV Et II-618 Ph AW Et II-619 Ph AX Et II-620 Ph AY Et II-621 Ph AZ Et II-622 Ph BA Et II-623 Ph BB Et II-624 Ph BC Et II-625 Ph BD Et II-626 Ph BE Et II-627 Ph BF Et II-628 Ph BG Et II-629 Ph BH Et II-630 Ph BI Et

Test Example Inhibition Test of Human Secretory Phospholipase A₂

Analytical Experiment

In order to identify and evaluate an inhibitor of recombinant human secretory phospholipase A₂, the following chromogenic assay is utilized. The assay herein has been applied for high volume screening wherein 96 well microtiterplate is used. A general explanation for such assay is described in “Analysis of Human Synovial Fluid Phospholipase A₂ on Short Chain Phosphatidylcholine-Mixed Micelles: Development of a Spectrophotometric Assay Suitable for a Micortiterplate Reader” (Analytical Biochemistry, 204, pp 190-197, 1992 by Laure. J. Reynolds. Lori L. Hughes and Edward A. Dennis: the disclosure of which is incorporated herein for reference.

Reagents:

Reaction Buffer

CaCl₂.6H₂O (2.19 g/L)

KCl (7.455 gL)

Bovine Serum Albumin (fatty acid free) (1 g/L) (Sigma A-7030)

Tris-HCl (3.94 g/L)

pH 7.5 (adjusted with NaOH)

Enzyme Buffer

0.05 M-AcONa

0.2 M-NaCl

pH 4.5 (adjusted with acetic acid)

Enzyme Solution

1 mg of sPLA₂ is dissolved in 1 ml of an enzyme buffer. Thereafter, the solution is maintained at 4° C.

In the assay, 5 μl of the solution is diluted with 1995 μl of the reaction buffer to be used.

DTNB

198 mg of 5,5′-dithiobis-2-benzoic acid (manufactured by Wako Pure Chemicals) is dissolved in 100 ml of H₂O

pH 7.5 (adjusted with NaOH)

Substrate Solution

100 mg of racemic 1,2-bis(heptanoylthio)-1,2-dideoxy-sn-glycero-3-phospholylcholine is dissolved in 1 ml of chloroform.

Triton-X 100

624.9 mg of Triton-X 100 is dissolved in the reaction buffer.

Enzyme Reaction: for 1 plate of Microtiterplate

1) 0.106 ml of the substrate solution is put in a centrifugal tube, and nitrogen gas is jetted to remove the solvent. 0.54 ml of Triton-X 100 is added thereto, the mixture is stirred, thereafter it is sonified in a bath type sonification to dissolve. To the resulting product are added 17.8 m1l of the reaction buffer and 0.46 ml of DTNB, and 0.18 ml each of the admixture is poured to wells of the 96 well microtiterplate.

2) 10 μl of a test compound (or solvent blank) are added in accordance with alignment of plates which has been previously set.

3) Incubation is effected at 40° C. for 15 minutes.

4) 20 μl of an enzyme solution (sPLA₂) which has been previously diluted (50 ng/well) are added to start reaction (40° C., 30 minutes).

5) Changes in absorbancy for 30 minutes are measured by a plate reader, and inhibition activity was calculated (OD: 405 nm).

6) IC₅₀ was determined by plotting log concentration with respect to inhibition values within 10% to 90% inhibiting range.

Results of the human secretory phospholipase A₂ inhibition test are shown in the following Table 18.

TABLE 18 Compound IC₅₀ No. (μM) I-1 0.248 I-2 0.009 I-3 0.013 I-4 0.150 I-5 0.011 I-6 0.238 I-7 0.223 I-8 0.184 I-9 0.165 I-10 0.296 I-11 0.067 I-12 0.745 I-13 0.238 I-14 0.883 I-15 0.097 I-16 0.012 I-17 0.007 I-18 0.010 I-19 0.010 I-20 0.019 I-21 0.006 I-22 0.022 I-23 0.007 I-24 0.021 I-25 0.006 I-26 0.177 I-27 0.126 I-28 I-29 1.517 I-30 4.521 I-31 15.630 I-32 0.239 I-33 0.072 I-34 0.058 I-35 0.111 I-36 0.102 I-37 0.212 I-38 0.227 I-39 0.079 I-40 0.099 I-41 0.064 I-42 0.026 I-43 0.154 I-44 0.315 I-45 0.030 I-46 0.268 I-47 0.618 I-48 0.211 I-49 7.811 I-50 0.526 I-51 25.589 I-52 0.093 I-53 3.741 I-54 0.148 I-55 0.056 I-56 0.052 I-57 0.007 I-58 0.009 I-59 1.078 I-60 0.365 I-61 2.610 I-62 0.012 I-63 0.006 I-64 0.007 I-65 0.007 I-66 0.006 I-67 0.016 I-68 0.025 I-69 0.008 I-70 0.009 I-71 0.008 I-72 0.009 I-73 0.019 I-74 0.015 I-75 0.009 I-76 0.006 I-77 0.010 I-78 0.005 I-79 0.464 I-80 0.013 I-81 8.186 I-82 0.093 I-83 0.083 I-84 0.008

Formulation Example

It is to be noted that the following Formulation Examples 1 to 8 are mere illustration, but not intended to limit the scope of the invention. The term “active ingredient” means the compounds represented by the formula (I), the prodrugs thereof, their pharmaceutical acceptable salts, or their solvates.

Formulation Example 1

Hard gelatin capsules are prepared using of the following ingredients:

Dose (mg/capsule) Active ingredient 250 Starch, dried 200 Magnesium stearate  10 Total 460 mg

Formulation Example 2

A tablet is prepared using of the following ingredients:

Dose (mg/tablet) Active ingredient 250 Cellulose, microcrystals 400 Silicon dioxide, fumed  10 Stearic acid  5 Total 665 mg

The components are blended and compressed to form tablets each weighing 665 mg.

Formulation Example 3

An aerosol solution is prepared containing the following components:

Weight Active ingredient 0.25 Ethanol 25.75 Propellant 22 (chlorodifluoromethane) 74.00 Total 100.00

The active compound is mixed with ethanol and the admixture added to a portion of the propellant 22, cooled to −30° C. and transferred to filling device. The required amount is then fed to stainless steel container and diluted with the reminder of the propellant. The valve units are then fitted to the container.

Formulation Example 4

Tablets, each containing 60 mg of active ingredient, are made as follows. Active ingredient 60 mg Starch 45 mg Microcrystals cellulose 35 mg Polyvinylpyrrolidone (as 10% solution in water) 4 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total 150 mg

The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve, and the mixed thoroughly. The aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powder, and the admixture then is passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.

Formulation Example 5

Active ingredient  80 mg Starch  59 mg Microcrystals cellulose  59 mg Magnesium stearate  2 mg Total 200 mg

The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.

Formulation Example 6

Active ingredient  225 mg Saturated fatty acid glycerides 2000 mg Total 2225 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.

Formulation Example 7

Suspensions, each containing 50 mg of active ingredient per 5 ml dose, are made as follows:

Active ingredient   50 mg Sodium carboxymethyl cellulose   50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor q.v. Color q.v. Purified water to total   5 ml

The active ingredient is passed through a No. 45 U.S. sieve, and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume.

Formulation Example 8

An intravenous formulation may be prepared as follows: Active ingredient  100 mg Isotonic saline 1000 ml

The solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute.

Formulation Example 9

Composition of lyophilized preparations (in 1 vial) is made as follows:

Active ingredient 127 mg Trisodium citrate dihydrate  36 mg Mannitol 180 mg

The above materials are dissolved in water for injection such that the concentration of Active ingredient is 10 mg/g. The primary freezing step is done for 3 hours at −40° C., the heat treating step for 10 hours at −10° C., and the re-freezing step for 3 hours at −40° C. Then, the primary drying step is performed for 60 hours at 0° C., 10 Pa and the secondary drying step for 5 hours at 60° C., 4 Pa. Thus the lyophilized preparation is obtained.

Industrial Applicability

The compounds according to the present invention have sPLA₂ inhibiting activity, so that the compounds of the invention inhibits sPLA₂-mediated fatty acid (such as arachidonic acid) release, whereby it is effective for treating septic shock and the like. 

What is claimed is:
 1. A compound represented by the formula (I):

wherein R¹ is methyl or a group represented by the formula:

wherein L⁶ is a bond or —O—; R¹³ and R¹⁴ are independently selected from the group consisting of halogen, C1 to C10 alkyl, C1 to C10 alkoxy, C1 to C10 alkylthio, aryl, thienyl, benzothienyl, thiazolyl, benzothiazolyl, oxazolyl, benzoxazolyl, and C1 to C10 haloalkyl; p and w aye independently an integer from 0 to 5, u is an integer from 0 to 4; R² is C1 to C4 alkyl; R³ is —O—(CH₂)_(k)—COOH, wherein k is an integer from 1 to 3; R⁴ is a hydrogen atom; R⁵ is selected from the group consisting of hydrogen atom, C1 to C6 alkyl, C7 to C12 aralkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, C1 to C6 hydroxyalkyl, C2 to C6 haloalkyloxy, halogen, carboxy, C1 to C6 alkyloxycarbonyl, axyloxy, aryloxy C1 to C8 alkyl, arylthio, arylthio C1 to C8 alkyl, cyano C1 to C8 alkyl, phenyl, cyclohexyl, 4-fluorophenyloxymethyl, trifluoromethyl, cbloromethyl, pyrrolidin-1-ylmethyl, morpholinomethyl, 4methylpiperazin-1-ylmethyl, 4-fluorophenyl, 4-methyloxyphenyl, cyclopentyl, benzodioxol-5-yl, methylthiomethyl, methyloxymethyl, 4-methyloxyphenyloxymethyl, 3,4-dimethyloxyphenyloxymethyl, 4-methylphenyloxymethyl, and 2,5-dioxopyrrolidin-1-ylmethyl; and R^(A) is a group represented by the formula:

wherein Z is —NH₂ or —NHNH₂, or a pharmaceutically acceptable salt, hydrate or ester thereof.
 2. A pyrrolo[1,2-b]pyridazine compound selected from the group consisting of: Methyl (5-aminooxalyl-7-benzyl-6-ethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, (5-aminooxalyl-7-benzyl-6-ethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid, Sodium (5-aminooxalyl-7-benzyl-6-ethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, Methyl (5-aminooxalyl-7-benzyl-6-ethyl-2-methylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, (5-aminooxalyl-7-benzyl-6-ethyl-2-methylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid, Methyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, Ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, 2-(Morpholine-4-yl)ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid, Sodium (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, Methyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid, Methyl [5-aminooxalyl-7-benzyl-6-ethyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy]acetate, [5-aminooxalyl-6-ehtyl-7-(2-flourobenzyl)-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid Methyl [5-aminooxalyl-7-benxyl-6-ethyl-2-(4-fluorobenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate, [5-aminooxalyl-6-ethyl-7-(2-fluorobenzyl)-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid, Methyl [5-aminooxalyl-7-benzyl-6-ethyl-2-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate, [5-aminooxalyl-7-benzyl-6-ethyl-2-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid, Methyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid, Methyl [5-aminooxalyl-7-benzyl-6-ethyl-2-(4-methoxyphenyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate, [5-aminooxalyl-7-benzyl-6-ethyl-2-(4-methoxyphenyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid, Methyl [5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate, [5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid, Methyl [5-aminooxalyl-6-ethyl-2-methyl-7-(3-phenoxybenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate, [5-aminooxalyl-6-ethyl-2-methyl-7-(3-phenoxybenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid, Methyl (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid, Methyl (5 -aminooxalyl-2,7-dibenzyl-6-methylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, (5-aminooxalyl-2,7-dibenzyl-6-methylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid, Methyl[5-aminooxalyl-2,6-dimethyl-7-[2-(4-fluorophenyl)benzyl]pyrrolo[1,2-b]pyridazine-4-yloxy]acetate, and [5-aminooxalyl-2,6-dimethyl-7-[2-(4-fluorophenyl)benzyl]pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid; or a pharmaceutically acceptable salt, hydrate or ester thereof.
 3. A pyrrolo[1,2-b]pyridazine compound selected from the group consisting of Methyl(5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, Ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, 2-(Morpholine-4-yl)ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, Sodium (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid, Methyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, Ethyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, 2-(Morpholine-4-yl)ethyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, Sodium (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid, Methyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, Ethyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, 2-(Morpholine-4-yl)ethyl 5 -aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, Sodium (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid, Methyl [5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate, Ethyl [5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate, 2-(Morpholine-4-yl)ethyl 5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy)acetate, Sodium [5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate, (5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid, Methyl (5 -aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, Ethyl (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, 2-(Morpholine-4-yl)ethyl 5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, Sodium (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, and (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid, or a pharmaceutically acceptable salt, hydrate or ester thereof.
 4. A compound represented by the formula (IV):

wherein R²⁰ is methyl or a group represented by the formula:

wherein L⁶ is a bond or —O—; R¹³ and R¹⁴ are independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, thienyl, benzothienyl, thiazolyl, benzothiazolyl, oxazolyl, benzoxazolyl, and C1 to C10 haloalkyl; p and w are independently an integer from 0 to 5, u is an integer from 0 to 4; R²¹ is C1 to C3 alkyl; R²³ is hydrogen atom, C1 to C6 alkyl, C7 to C12 aralkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, C1 to C6 hydroxyalkyl, C2 to C6 haloalkyloxy, halogen, carboxy, C1 to C6 alkyloxycarbonyl, aryloxy, aryloxy C1 to C8 alkyl, arylthio, arylthio C1 to C8 alkyl, cyano C1 to C8 alkyl, phenyl, cyclohexyl; R^(B) is a group represented by the formula:

wherein Z is —NH₂ or —NHNH₂; and k is an integer from 1 to 3; or a pharmaceutically acceptable salt, hydrate or ester thereof.
 5. A pharmaceutical composition for sepsis or septic shock containing a compound as claimed in claim 1 as an active ingredient in combination with a pharmaceutically acceptable carrier.
 6. A method of treating a human or non-human mammal, to alleviate the pathological effects of sepsis and septic shock; wherein the method comprises administration to said mammal of a pyrrolo[1,2-b]pyridazine compound as claimed in claim 1 in a pharmaceutically effective amount.
 7. A method of treating a mammal, to alleviate the pathological effects of sepsis or septic shock; wherein the method comprises administration to said mammal of a pyrrolo[1,2-b]pyridazine compound as claimed in claim 1 in a pharmaceutically effective amount. 